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Objectives: The immunologic profile and opportunistic viral DNA increase were monitored in Italian patients with COVID-19 in order to identify markers of disease severity. Methods: A total of 104 patients infected with SARS-CoV-2 were evaluated in the study. Of them, 42/104 (40.4%) were hospitalized in an intensive care unit (ICU) and 62/104(59.6%) in a sub-intensive care unit (SICU). Human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), Parvovirus B19 and Human Herpesvirus 6 virus reactivations were determined by real-time PCR, and lymphocyte subpopulation counts were determined by flow cytometry. Results: Among opportunistic viruses, only EBV was consistently detected. EBV DNA was observed in 40/42 (95.2%) of the ICU patients and in 51/61 (83.6%) of the SICU patients. Comparing the two groups of patients, the EBV DNA median level among ICU patients was significantly higher than that observed in SICU patients. In parallel, a significant reduction of CD8 T cell and NK count in ICU patients as compared with SICU patients was observed (p

Antimicrobial resistance in Gram-negative bacteria, particularly Enterobacteriaceae, has become a leading cause of morbidity and mortality and a serious public health concern. Gram-negative bacteria carrying extended-spectrum beta-lactamase (ESBL) enzymes now represent a significant proportion of all bacteria isolated from different countries worldwide. Furthermore, the increasing number of isolates carrying carbapenemases in recent years includes multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacteria. Here, we describe what, to our knowledge, is the first case of a patient with a prosthetic joint infection from carbapenemase-resistant Klebsiella pneumoniae (CRKP) successfully treated with ceftazidime-avibactam in Italy.

Background: Daptomycin pharmacokinetics and pharmacodynamics data relative to higher doses in patients are necessary for clinical practice., Objectives: A monocentric, prospective study that enrolled patients with a diagnosis of Staphylococcus spp. infective endocarditis treated with daptomycin according to clinical practice, to evaluate the pharmacokinetics/pharmacodynamics of different daptomycin daily doses (group A: 8-10 and group B: 11-12 mg/kg)., Design and Methods: A monocentric, prospective, cohort study that enrolled patients with a diagnosis of Staphylococcus spp. infective endocarditis treated with daptomycin. Daptomycin was administered by intravenous infusion over a 30-min period for at least five consecutive days before PK study., Results: Twenty-two patients were included. Native valve infectious endocarditis (IE) was diagnosed in 9 patients, prosthetic valve IE was diagnosed in 10 patients and 3 patients had concomitant intracardiac device infections. All patients showed a microbiologic response with negative blood cultures by day 5 (1-3 interquartile rate (IQR) 3-8). The median calculated AUC 0-24 was 1298 (1-3 IQR 1069-1484) and 1459 (1-3 IQR 1218-1711) µg*h/mL, with the corresponding clearance of 0.49 (1-3 IQR 0.37-0.57) and 0.57 (1-3 IQR 0.40-0.71) L/h, respectively. A value of area under the curve/minimum inhibitory concentration (AUC/MIC) > 666 was reached by all patients; however, 4 out of 15 patients in group A and 1 out of 14 patients in group B did not reach the pharmacokinetic/pharmacodynamic (PK/PD) target of 1061; therefore, AUC/MIC equal to or above 1061 was reached by 73.3% in group A and 92.9% in group B., Conclusion: From a PK/PD point of view, all patients reached the value of AUC/MIC > 666, while roughly 70% of patients in group A and 90% in group B reached the target value of AUC/MIC>1061. Even if this cut-off value is arbitrary, 11-12 mg/kg daily dose could be taken into consideration in case of serious infections characterised by a high inoculum or in cases of prosthetic valve infections., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2025.)

Graft infection, fistula, and mediastinitis are reported among the serious cardiovascular complications after a Bentall procedure. Surgery associated with antimicrobial treatment is usually recommended but not easily feasible in most cases. In this report, we describe a case of successful valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) in a patient with a degenerated bioconduit from a previously healed infectious endocarditis (IE). The TAVR procedure has been demonstrated to be a therapeutic option in selected cases with a previous history of IE who have been fully treated with antimicrobial therapy and who present a low risk of local re-infection and are deemed at prohibitive or high risk for surgical replacement. Data on TAVR on a bioconduit after a Bentall procedure are scarce. The present case underlines that a long follow-up and individualized treatment could improve the prognosis in patients with a history of prosthetic valve and aortic graft infection and severe valve dysfunction who cannot undergo surgical treatment. The 18F-labeled fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) result could be successfully employed in the decision algorithm. Long-term antibiotic treatment, which could be lifelong in some instances, could be a reasonable choice when the risk of recurrence is associated with the risk for the patient's life., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Aiello et al.)

Background: Daptomycin is a cyclic lipopeptide antibiotic used to treat serious infectious endocarditis caused by Staphylococcus aureus . The pharmacodynamic parameter correlating best with efficacy is the ratio of the estimated area under the concentration (AUC 0-24 )-time curve to the minimum inhibitory concentration. The aim of the study is to develop a limited sampling strategy to estimate AUC 0-24 using a reduced number of samples., Methods: Sixty-eight daptomycin AUC 0-24 values were calculated for 50 White patients who underwent treatment for at least 5 consecutive days. Plasma concentrations were detected using a validated high-performance liquid chromatography-tandem mass spectrometry analytical method, with daptomycin-d5 as an internal standard. Multiple regression was used to evaluate the ability of 2 concentration-time points to predict the AUC 0-24 calculated from the entire pharmacokinetic profile. Prediction bias was calculated as the mean prediction error, whereas prediction precision was estimated as the mean absolute prediction error. The development and validation datasets comprised 40 and 10 randomly selected patients, respectively., Results: The AUC 0-24 (mg*h/L) was best estimated using the daptomycin trough concentration and plasma concentrations detected 2 hours after dosing. We calculated a mean prediction error of 1.6 (95% confidence interval, -10.7 to 10.9) and a mean absolute prediction error of 11.8 (95% confidence interval, 5.3-18.3), with 73% of prediction errors within ±15%., Conclusions: An equation was developed to estimate daptomycin exposure (AUC 0-24 ), offering clinical applicability and utility in generating personalized dosing regimens, especially for individuals at high risk of treatment failure or delayed response., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Intravenous drug users (IVDUs) face heightened susceptibility to life-threatening gram-positive bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA). While the standard antibiotic dosing strategies for special patients, such as obese or critically ill individuals, are known to be inadequate, raising concerns about treatment efficacy, a similar sort of understanding has not been assessed for IVDUs yet. With this in mind, this review examines the pharmacokinetic/pharmacodynamic characteristics of antibiotics commonly used against gram-positive bacteria in IVDUs. Focusing on daptomycin, vancomycin, teicoplanin, aminoglycosides, and the novel lipoglycopeptide dalbavancin, the study reveals significant pharmacokinetic variations in IVDUs, suggesting the need for personalized dosing. Concomitant opioid substitution therapy and other factors, such as malnutrition, contribute to altered pharmacokinetics/pharmacodynamics, emphasizing the importance of targeted therapeutic drug monitoring. Overall, our study calls for increased awareness among clinicians regarding the unique pharmacokinetic/pharmacodynamic challenges in IVDUs and advocates for tailored antibiotic dosing strategies to enhance treatment outcomes in this marginalized population., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In this study, we present two cases of Klebsiella pneumoniae , one KPC-33- and one NDM-1-producing, showing resistance to cefiderocol and ceftazidime/avibactam, collected in the intensive care unit of a hospital in Northern Italy from two patients who had recently undergone lung transplantation. Whole-genome sequencing was performed to investigate the molecular features of these strains.

Introduction: long term suppressive antibiotic treatment may be the only feasible option for patients with infective endocarditis (IE) not suitable for surgery., Case Reports: we present three cases of prosthetic valve endocarditis (PVE) caused by Enterococcus faecalis and Streptococcus gallolyticus which could not undergo surgical intervention due to high risk. Despite this, patients were successfully managed only by medical approach. Following intravenous targeted antimicrobial therapy, patients received chronic suppressive antimicrobial therapy (SAT) for at least twelve months with oral amoxicillin. In all cases, no further febrile episodes nor bacteraemia were observed and in two cases a complete positron emission tomography (PET) response was achieved. Due to a priori uncertainty about antimicrobial exposure during oral SAT, serum bactericidal titres (SBTs) were obtained and compared to those obtained during parenteral therapy., Conclusions: long term oral amoxicillin was effective and well-tolerated. SBTs after switch to oral therapy were quite heterogeneous, in some cases not reaching the conventionally established titre to assess bactericidal effect (1:8).Key pointsendovascular infection in non-suitable-for-surgery patients can be managed with long-term oral suppressive therapy.serum bactericidal assay confirmed high effectiveness of parenteral antibiotic therapy.serum bactericidal assay showed highly variable titres during oral therapy.

Background: The aim of our survey was to analyze the current attitudes toward antimicrobial prophylaxis in heart transplanting centers worldwide., Methods: The survey was composed of a total of 50 questions, it consisted of four different sections as follows. The first section collected physicians' personal data and centers' general characteristics, second assessed the approach to patients colonized with multidrug-resistant organisms (MDROs), while the third consisted of the infection risk related to cardiovascular devices, and antimicrobial treatment data, the last focused on donor's colonization., Results: A total of 56 answers from 26 different countries were collected, mostly from Europe (n = 30) and the USA (n = 16). A first-generation cephalosporin (58.9%) or a combination therapy with vancomycin (10.7%) were the most frequently prescribed antimicrobial prophylaxis. Roughly 30% of the centers used different antimicrobial prophylaxis,mostly including Gram negative bacteria coverage. The frequency of screening for multidrug resistant Gram-negative bacteria was higher in Europe, where the percentage of centers providing screening for extended spectrum beta-lactamase (46.7%) and carbapenem-resistant Enterobacteriaceae (CRE) (53.3%) was higher than in other geographic area (p = .019; p = .013, respectively)., Conclusion: This survey highlights a heterogeneity of clinical practice concerning antimicrobial prophylaxis at transplant. The concern for potential Gram-negative bacteria infection was responsible for broader antimicrobial coverage in 30% of centers., (© 2023 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

The emergency room (ER) is the first gateway for patients with sepsis to inpatient units, and identifying best practices and benchmarks to be applied in this setting might crucially result in better patient's outcomes. In this study, we want to evaluate the results in terms of decreased the in-hospital mortality of patients with sepsis of a Sepsis Project developed in the ER. All patients admitted to the ER of our Hospital from the 1st January, 2016 to the 31stJuly 2019 with suspect of sepsis (MEWS score ≥ of 3) and positive blood culture upon ER admission were included in this retrospective observational study. The study comprises of two periods: Period A: From the 1st Jan 2016 to the 31st Dec 2017, before the implementation of the Sepsis project. Period B: From the 1st Jan 2018 to the 31stJul 2019, after the implementation of the Sepsis project. To analyze the difference in mortality between the two periods, a univariate and multivariate logistic regression was used. The risk of in-hospital mortality was expressed as an odds ratio (OR) and a 95% confidence interval (95% CI). Overall, 722 patients admitted in ER had positive BC on admissions, 408 in period A and 314 in period B. In-hospital mortality was 18.9% in period A and 12.7% in period B (p = 0.03). At multivariable analysis, mortality was still reduced in period B compared to period A (OR 0.64, 95% CI 0.41-0.98; p = 0.045). Having an infection due to GP bacteria or polymicrobial was associated with an increased risk of death, as it was having a neoplasm or diabetes. A marked reduction in in-hospital mortality of patients with documented BSI associated with signs or symptoms of sepsis after the implementation of a sepsis project based on the application of sepsis bundles in the ER., (© 2023. The Author(s).)

Background: The use of steroid therapy in potentially life-threatening neuroinvasive forms of West Nile infection (WNND) is controversial. The aim of this study is to assess the efficacy of steroid therapy in reducing intrahospital mortality, length of stay, and neurological sequelae at discharge., Methods: This was a multicenter, retrospective, observational study conducted in 5 hospitals in Northern Italy, headed by the Fondazione IRCSS Policlinico San Matteo (Pavia). We extracted all patient data with WNND diagnoses, comparing patients who received steroid treatment with patients who did not receive steroid treatment between January 2014 and January 2022. Comparisons between the 2 groups were performed using chi-square tests for categorical variables and Mann-Whitney tests for non-normal continuous data, and a generalized linear model for the binomial family was carried out., Results: Data from 65 WNND patients were extracted. Among these patients, 33 (50.7%) received steroid therapy at any point during their hospitalization. Receiving steroid therapy did not significantly reduce intrahospital mortality (odds ratio [OR], 1.70; 95% CI, 0.3-13.8; P = .89) or neurological sequelae at discharge (OR, 0.53; 95% CI, 0.16-1.76; P = .47)., Conclusions: Steroid treatment is currently used on a single-case basis in severe WNND. More prospective data are needed to demonstrate a protective effect on mortality and neurological sequelae., Competing Interests: Potential conflicts of interest. All authors: no reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

SARS-CoV-2 and flu may lead to severe acute respiratory distress syndrome (ARDS) requiring extracorporeal membrane oxygenation (ECMO). The aim of the present study is to compare the incidence of bloodstream infections (BSIs) and outcome in patients with flu and SARS-CoV-2 infection hospitalized in ICU and undergoing ECMO. This study is a retrospective analysis of the San Matteo COVID-19 Registry (SMACORE) cohort. The study was conducted from January 2018 to April 2020. Demographic data and microbiological data were recorded during hospitalization. BSIs occurring during ECMO were analyzed. Eighteen patients treated with ECMO, 22 subjects with SARS-CoV-2 infection and 7 with flu, median age 61years for SARS-CoV-2 and 50 for flu (p=NS). Median ECMO duration was similar in the two pathologies. Median time to bloodstream infection from ECMO initiation was similar. Bloodstream infection incidence rate was 2.65 per 100 patients/days for flu and 2.2 per 100 patients/days for SARS-CoV-2. Global infection rate was 5 per 100 patients/days for SARS-CoV-2 patients and 5.3 per 100 patients/days for flu. Mortality during ECMO was 40.9% (5 out of 22 patients) for SARS-CoV-2 infection while none died among flu patients. ECMO-associated mortality was higher in SARS-CoV-2 infection compared with flu infection.

The immunogenicity of severe acute respiratory syndrome 2 virus (SARS-CoV-2) vaccines in immunocompromised patients remains to be further explored. Here, we evaluated the immunogenicity elicited by complete vaccination with BNT162b2 vaccine in solid organ transplant recipients (SOTRs). A cohort of 110 SOTRs from Northern Italy were vaccinated with two doses of BNT162b2 mRNA vaccine and prospectively monitored at baseline and after 42 days. Both SARS-CoV-2 naïve and recovered subjects were included. Humoral response elicited by vaccination, including SARS-CoV-2 neutralizing antibodies (SARS-CoV-2 NT Abs), was evaluated; additionally, ex-vivo ELISpot assay was performed for the quantification of Spike-specific T-cell response. Results were compared with those obtained in a cohort of healthy subjects. In a subset of patients, humoral and T-cell responses against delta variant were also evaluated. Less than 20% of transplanted subjects developed a positive humoral and cell-mediated response after complete vaccination schedule. Overall, median levels of immune response elicited by vaccination were significantly lower with respect to controls in SARS-CoV-2 naïve transplant, but not in SARS-CoV-2 recovered transplanted patients. Additionally, a significant impairment of both humoral and cell-mediated response was observed in mycophenolate-treated patients. Positive delta-SARS-CoV-2 NT Abs levels were detected in almost all the SARS-CoV-2 recovered subjects but not in previously uninfected patients. Our study supports previous observations of a low level of seroconversion after vaccination in transplanted patients.

The development and persistence of SARS-CoV-2-specific immune response in immunocompetent (IC) and immunocompromised patients is crucial for long-term protection. Immune response to SARS-CoV-2 infection was analysed in 57 IC and 15 solid organ transplanted (TX) patients. Antibody responses were determined by ELISA and neutralization assay. T-cell response was determined by stimulation with peptide pools of the Spike, Envelope, Membrane, and Nucleocapsid proteins with a 20-h Activation Induced Marker (AIM) and 7-day lymphoproliferative assays. Antibody response was detected at similar levels in IC and TX patients. Anti-Spike IgG, IgA and neutralizing antibodies persisted for at least one year, while anti-Nucleocapsid IgG declined earlier. Patients with pneumonia developed higher antibody levels than patients with mild symptoms. Similarly, both rapid and proliferative T-cell responses were detected within the first two months after infection at comparable levels in IC and TX patients, and were higher in patients with pneumonia. T-cell response persisted for at least one year in both IC and TX patients. Spike, Membrane, and Nucleocapsid proteins elicited the major CD4 + and CD8 + T-cell responses, whereas the T-cell response to Envelope protein was negligible. After SARS-CoV-2 infection, antibody and T-cell responses develop rapidly and persist over time in both immunocompetent and transplanted patients.

Background and Objective: When administered for severe infections in intravenous drug users (IDUs) at a daily dose of 6 mg/kg, daptomycin displayed abnormal pharmacokinetic parameters compared with those seen in healthy volunteers; specifically, decreased trough and maximum concentrations (C trough ; C max ) and increased clearance (CL). The objective of this study was to evaluate the pharmacokinetics and pharmacodynamics of daptomycin administered at a daily dosage of 12 mg/kg for Staphylococcus aureus infective endocarditis (IE) in patients concomitantly treated with methadone, and to compare the results with those published in the literature for healthy controls treated with the same daily dose., Methods: Antibiotic treatment included daptomycin (12 mg/kg daily) in combination with an antistaphylococcal β-lactam (cefazolin 2 g three times a day). The minimum inhibitory concentration (MIC) of Staphylococcus aureus isolated through blood cultures was used to calculate pharmacokinetic and pharmacodynamic parameters such as the ratio of the area under the concentration-time curve over 24 h to the MIC (AUC 0-24 /MIC) and C max /MIC., Results: Five IDUs hospitalized for IE were enrolled. The mean measured daptomycin C max and C trough were 54.1 μg/mL (CV: 0.32) and 8.7 μg/mL (CV: 0.59), respectively; the mean calculated AUC 0-24 was 742.7 μg × h/mL (CV: 0.31). The estimated average volume of distribution at the steady state (V d,ss ) and the half-life (t 1/2 ) were 316.5 mL/kg (CV: 0.53) and 14.4 h (CV: 0.30), respectively. The mean daptomycin clearance from plasma normalized for body weight (CL wp ) was 17.3 mL/(h × kg) (CV: 0.33). The calculated average C max and AUC 0-24 (183.7 µg/mL and 1277.4 µg × h/mL, respectively) were lower than and statistically significantly different from (p < 0.001 and p = 0.001, respectively) those expected for healthy volunteers., Conclusions: Treatment of Staphylococcus aureus IE in IDUs on methadone treatment requires the use of high daptomycin daily doses in order to achieve satisfactory pharmacodynamic parameters. Close monitoring of the daptomycin plasma concentration is suggested., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Progressive multifocal leukoencephalopathy (PML) is still burdened by high mortality in a subset of patients, such as those affected by hematological malignancies. The aim of this study was to analyze the safety and carry out preliminary evaluation of the efficacy of polyomavirus JC (JCPyV)-specific T cell therapy in a cohort of hematological patients with PML., Methods: Between 2014 and 2019, 9 patients with a diagnosis of "definite PML" according to the 2013 consensus who were showing progressive clinical deterioration received JCPyV-specific T cells. Cell lines were expanded from autologous or allogenic peripheral blood mononuclear cells by stimulation with JCPyV antigen-derived peptides., Results: None of the patients experienced treatment-related adverse events. In the evaluable patients, an increase in the frequency of circulating JCPyV-specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid. In responsive patients, transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, which was interpreted as a sign of immune control and which regressed spontaneously without the need for steroid treatment. Six of 9 patients achieved PML control, with 5 alive and in good clinical condition at their last follow-up., Interpretation: Among other novel treatments, T cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity. Neurologists should be encouraged to refer PML patients to specialized centers to allow access to this treatment strategy. ANN NEUROL 2021;89:769-779., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Nocardia has always been considered a pathogen of the immunocompromised host, but recent evidence has also highlighted its role as a pathogen in the immunocompetent. We aim to assess the role of immunosuppression in the disease. We reviewed all the cases of infections due to Nocardia spp. in our center that occurred from 1 January 2012 to 30 September 2019. Patients were divided into three groups: typical immunocompromised (PLWHIV, solid organ or hematopoietic cell transplant recipients, individuals under immunosuppressive drugs), atypical immunocompromised (ongoing chronic diseases involving the lung, kidney, liver and diabetes) and immunocompetent. We identified 53 patients with an infection by Nocardia spp. Thirty-four (60.4%) of them were immunocompromised, 22 (64.7%) typical and 12 (35.3%) atypical immunocompromised. Nineteen (35.8%) were immunocompetent. The two conditions most frequently associated with infection were chronic lung disease (41.5%) and ongoing treatment with immunosuppressive drugs (33.9%). In our cohort a remarkable prevalence of nocardiosis in immunocompetent and atypical immunosuppressed patients was observed.

Patients with Corynebacterium striatum endocarditis are usually managed with long-term intravenous antibiotic therapy and hospitalization. Here we describe a case of a 76-year-old woman with hepatitis C virus (HCV) related cirrhosis who developed endocarditis due to Corynebacterium striatum associated with severe aortic regurgitation. To our knowledge, this is the first case to be successfully treated with an early switch to oral linezolid after three weeks of vancomycin. We performed a literature review using the PubMed database and found 27 cases which showed the enhanced virulence of this pathogen especially for long-term hospitalized patients with a frequent need of surgical treatment (44.4%) and long course of parenteral antimicrobial therapy, with vancomycin as drug of choice. There are no studies confirming the possibility of using oral treatment in non-diphtheritic Corynebacteria infective endocarditis. This case report provides us with the evidence that once the patient is in a stable condition, the efficacy and safety of linezolid might be similar to vancomycin administration. New trials and prospective studies are needed to confirm the opportunity of an early switch to oral therapy in this specific setting.

Background: Ventriculoatrial shunts were one of the most common treatments of hydrocephalus in pediatric and adult patients up to about 40 years ago. Thereafter, due to the widespread recognition of the severe cardiac and renal complications associated with ventriculoatrial shunts, they are almost exclusively implanted when other techniques fail. However, late infection or atrial thrombi of previously implanted shunts require removal of the atrial catheter several decades after implantation. Techniques derived from management of central venous access catheters can avoid cardiothoracic surgery in such instances., Methods: We retrospectively investigated all the patients requiring removal of a VA shunt for complications treated in the last 5 years in our institution., Results: We identified two patients that were implanted 28 and 40 years earlier. Both developed endocarditis with a large atrial thrombus and were successfully treated endovascularly. The successful percutaneous removal was achieved by applying, for the first time in this setting, the endoluminal dilation technique as proposed by Hong. After ventriculoatrial shunt removal and its substitution with an external drainage, both patients where successfully weaned from the need for a shunt and their infection resolved., Conclusion: Patients carrying a ventriculoatrial shunt are now rarely seen and awareness of long-term ventriculoatrial shunt complications is decreasing. However, these complications must be recognized and treated by shunt removal. Endovascular techniques are appropriate even in the presence of overt endocarditis, atrial thrombi, and tight adherence to the endocardial wall. Moreover, weaning from shunt dependence is possible even decades after shunting.

An accurate prediction of the clinical outcomes of European patients requiring hospitalisation for Coronavirus Disease 2019 (COVID-19) is lacking. The aim of the study is to identify predictors of in-hospital mortality and discharge in a cohort of Lombardy patients with COVID-19. All consecutive hospitalised patients from February 21st to March 30th, 2020, with confirmed COVID-19 from the IRCCS Policlinico San Matteo, Pavia, Lombardy, Italy, were included. In-hospital mortality and discharge were evaluated by competing risk analysis. The Fine and Gray model was fitted in order to estimate the effect of covariates on the cumulative incidence functions (CIFs) for in-hospital mortality and discharge. 426 adult patients [median age 68 (IQR 56 to 77 years)] were admitted with confirmed COVID-19 over a 5-week period; 292 (69%) were male. By 21 April 2020, 141 (33%) of these patients had died, 239 (56%) patients had been discharged and 46 (11%) were still hospitalised. Among these 46 patients, updated as of 30 May, 2020, 5 (10.9%) had died, 8 (17.4%) were still in ICU, 12 (26.1%) were transferred to lower intensity care units and 21 (45.7%) were discharged. Regression on the CIFs for in-hospital mortality showed that older age, male sex, number of comorbidities and hospital admission after March 4th were independent risk factors associated with in-hospital mortality. Older age, male sex and number of comorbidities definitively predicted in-hospital mortality in hospitalised patients with COVID-19.

Hyperimmune plasma from Covid-19 convalescent is a potential treatment for severe Covid-19. We conducted a multicenter one arm proof of concept interventional study. Patients with Covid-19 disease with moderate-to-severe Acute Respiratory Distress Syndrome, elevated C-reactive Protein and need for mechanical ventilation and/or CPAP were enrolled. One to three 250-300 ml unit of hyperimmune plasma (neutralizing antibodies titer ≥1:160) were administered. Primary outcome was 7-days hospital mortality. Secondary outcomes were PaO2/FiO2, laboratory and radiologic changes, as well as weaning from mechanical ventilation and safety. The study observed 46 patients from March, 25 to April, 21 2020. Patients were aged 63, 61% male, of them, 30 were on CPAP and 7 intubated. PaO2/FiO2 was 128 (SD 47). Bilateral infiltrates on chest X-ray was present in 36 patients (84%). Symptoms and ARDS duration were 14 (SD 7) and 6 days (SD 3). Three patients (6.5%) died within 7 days as compared to an expected 15% from the National Statistics and 30% from a small concurrent cohort of 23 patients. The upper one-sided 90%CI was 13.9%, allowing to reject the null hypothesis of a 15% mortality. PaO2/FiO2 increased by 112 units (95%CI 82 to142) in survivors, the chest radiogram severity decreased in 23% (95%CI 5% to 42%); CRP, Ferritin and LDH decreased by 60, 36 and 20% respectively. Weaning from CPAP was obtained in 26/30 patients and 3/7 were extubated. Five serious adverse events occurred in 4 patients (2 likely, 2 possible treatment related). In conclusion, Hyperimmune plasma in Covid-19 shows promising benefits, to be confirmed in a randomized controlled trial. This proof of concept study could open to future developments including hyperimmune plasma banking, development of standardized pharmaceutical products and monoclonal antibodies.

Liver impairment is frequent in patients with novel coronavirus disease (COVID-19) and direct viral tropism for the liver has been proven. Since several of the currently administered drugs against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are possibly hepatotoxic, the management of patients with COVID-19 and liver failure is still an almost unexplored field. Taking this challenging case of acute HBV with persistent hyperbilirubinemia and SARS-COV-2 infection with respiratory distress as a starting point, we here loop through this condition. Where the available therapeutic options are scarce, we here propose hemoperfusion (HP) as an attractive alternative to both delay any late-stage progression of hyper inflammation process in COVID-19 and remove the toxins involved in acute liver failure., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background and Aims: Obesity has been suggested as a possible risk factor for a more severe course of COVID-19; however, conclusive evidence is lacking and few studies have investigated the role of BMI as a risk factor for admission to intensive care unit (ICU) and mortality. We retrospectively analyzed a COVID-19 cohort recruited during the first 40 days of the epidemic in Italy. We examined the association between obesity and 30-day mortality, admission to ICU, mortality and length of hospital stay in patients with COVID-19., Methods and Results: Demographic, clinical and outcome data were retrospectively analyzed in 331 patients with COVID-19 admitted to hospital between 21 February and 31 March 2020. The predictive effect of obesity on mortality was assessed using a Cox proportional-hazard regression model, its effect on ICU admission and mortality in the ICU using logistic regressions, and its effect on length of hospital stay using a linear regression. Seventy-four of 331 patients had a BMI ≥30 kg/m 2 . Among obese patients, 21 (28.4%) required admission in ICU and 25 died (33.8%). After controlling for sex, age, comorbidities and clinical data, obesity was not significantly associated with mortality, mortality in ICU and length of hospital stay. The effect of obesity on ICU admission remained significant after controlling for sex, age, interstitial lung disease, heart disease and serum C-reactive protein., Conclusions: Obese patients with COVID-19 were more likely to be admitted to ICU than non-obese patients. However, there were no significant differences in mortality between the two groups., (Copyright © 2020 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Since the end of 2019, a new coronavirus strain has been reported in the Chinese province of Wuhan, indicated as 2019-nCoV or SARS-CoV-2. In February 2020, the first case of transmission on Italian soil was reported. On March 09, 2020, at the time of protocol design, the Italian Ministry of Health reported 10,149 people who had contracted the virus; of these, 8514 were positive, of which 5038 were hospitalized with symptoms (59.2%) and 877 in intensive care (10.3%), while the remaining 2599 were in home isolation; 631 were deceased (6.2%) and 1004 healed (9.9%). To date there are no studies in the literature that demonstrate its feasibility and efficacy in the context of the worldwide SARS-CoV-2 epidemic. Based upon the little existing evidence, we planned to assess the efficacy of the infusion of hyperimmune plasma in COVID-19 patients in a one-arm proof-of-concept clinical trial. The primary objective of our study is to evaluate the efficacy of the administration of plasma taken from convalescent donors of COVID-19 to critically ill patients with COVID-19 in terms of their survival. Death from any cause will be considered. The main limit of this study is its one-arm proof-of-concept design with only 43 patients enrolled. However, in the absence of previous evidence, larger and/or randomized trials did not appear to be ethically acceptable. Moreover, the results from this study, if encouraging, will allow us to plan further informed large clinical trials. Trial registration: NCT04321421 March 23, 2020.

Objectives: To detect possible severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA contamination of inanimate surfaces in areas at high risk of aerosol formation by patients with coronavirus disease 2019 (COVID-19)., Methods: Sampling was performed in the emergency unit and the sub-intensive care ward. SARS-CoV-2 RNA was extracted from swabbed surfaces and objects and subjected to real-time RT-PCR targeting RNA-dependent RNA polymerase and E genes. Virus isolation from positive samples was attempted in vitro on Vero E6 cells., Results: Twenty-six samples were collected and only two were positive for low-level SARS-CoV-2 RNA, both collected on the external surface of continuous positive airway pressure helmets. All transport media were inoculated onto susceptible cells, but none induced a cytopathic effect on day 7 of culture., Conclusions: Even though daily contact with inanimate surfaces and patient fomites in contaminated areas may be a medium of infection, our data obtained in real-life conditions suggest that it might be less extensive than hitherto recognized., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The clinical manifestation of COVID-19 can vary from an asymptomatic course to ARDS requiring invasive mechanical ventilation and extracorporeal membrane oxygenation. A kidney transplanted patient infected with SARS CoV-2 infection showed a mild disease despite immune suppression. It is possible that Immunosuppression can "be protective" as the cytokine storm is an important factor in the disease story. Despite the good outcome reported in the present case report, is remains of vital importance the solid organ transplant patients use precautions in order to avoid the infection., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

The role of immunosuppression in SARS-CoV-2-related disease (COVID-19) is a matter of debate. We here describe the course and the outcome of COVID-19 in a cohort of patients undergoing treatment with calcineurin inhibitors. In this monocentric cohort study, data were collected from the COVID-19 outbreak in Italy up to April 28 th 2020. Patients were followed at our hospital for solid organ transplantation or systemic rheumatic disorders (RMDs) and were on calcineurin inhibitor (CNI)-based therapy. Selected patients were referred from the North of Italy. The aim of our study was to evaluate the clinical course of COVID-19 in this setting. We evaluated 385 consecutive patients (220 males, 57%; median age 61 years, IQR 48-69); 331 (86%) received solid organ transplantation and 54 (14%) had a RMD. CNIs were the only immunosuppressant administered in 47 patients (12%). We identified 14 (4%) COVID-19 patients, all transplanted, mainly presenting with fever (86%) and diarrhea (71%). Twelve patients were hospitalized and two of them died, both with severe comorbidities. No patients developed acute respiratory distress syndrome or infectious complications. The surviving 10 patients are now fully recovered. The clinical course of COVID-19 patients on CNIs is generally mild, and the risk of superinfection seems low.

Tuberculosis (TB) caused by resistant strains is becoming a public health concern also in high-income countries. In Pavia province, Northern Italy, the prevalence of foreign-born has increased in recent years. Nevertheless, it is unclear if this has modified epidemiology and resistance patterns of Mycobacterium tuberculosis. We retrospectively collected data on all the Mycobacterium tuberculosis strains isolated by culture in the microbiology reference laboratory of the province of Pavia from 01/01/1998 to 31/12/2017. Overall, 919 patients were identified, 320 were foreign-born (34.8%). The proportion of cases due to foreign-born patients increased during the study period as did resistance to isoniazid (INH) (p = 0.01), while resistance to rifampicin (RIF) did not (p = 0.8). INH and RIF resistance were comparable among Italian and foreign-born patients (7.9% vs 9.7% for INH and 4% vs 5% for RIF, respectively). Twenty-height (3.05%) patients harboured MDR strains. Prevalence of MDR strains was not different between Italians and foreign-born patients (2.8% vs 3.4%, p = 0.6). During the study period the proportion of TB cases due to foreign-born patients and INH resistance increased. This increase was equal among Italian and foreign-born patients. Migrants in our area are not a driver of resistance to anti-mycobacterial drugs.

We describe clinical characteristics, treatments and outcomes of 44 Caucasian patients with coronavirus disease (COVID-19) at a single hospital in Pavia, Italy, from 21-28 February 2020, at the beginning of the outbreak in Europe. Seventeen patients developed severe disease, two died. After a median of 6 days, 14 patients were discharged from hospital. Predictors of lower odds of discharge were age > 65 years, antiviral treatment and for severe disease, lactate dehydrogenase > 300 mg/dL.

Background: We analyzed the impact of continuous/extended infusion (C/EI) vs intermittent infusion of piperacillin-tazobactam (TZP) and carbapenems on 30-day mortality of patients with liver cirrhosis and bloodstream infection (BSI)., Methods: The BICRHOME study was a prospective, multicenter study that enrolled 312 cirrhotic patients with BSI. In this secondary analysis, we selected patients receiving TZP or carbapenems as adequate empirical treatment. The 30-day mortality of patients receiving C/EI or intermittent infusion of TZP or carbapenems was assessed with Kaplan-Meier curves, Cox-regression model, and estimation of the average treatment effect (ATE) using propensity score matching., Results: Overall, 119 patients received TZP or carbapenems as empirical treatment. Patients who received C/EI had a significantly lower mortality rate (16% vs 36%, P = .047). In a Cox-regression model, the administration of C/EI was associated with a significantly lower mortality (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.11-0.936; P = .04) when adjusted for severity of illness and an ATE of 25.6% reduction in 30-day mortality risk (95% CI, 18.9-32.3; P < .0001) estimated with propensity score matching. A significant reduction in 30-day mortality was also observed in the subgroups of patients with sepsis (HR, 0.21; 95% CI, 0.06-0.74), acute-on-chronic liver failure (HR, 0.29; 95% CI, 0.03-0.99), and a model for end-stage liver disease score ≥25 (HR, 0.26; 95% CI, 0.08-0.92). At competing risk analysis, C/EI of beta-lactams was associated with significantly higher rates of hospital discharge (subdistribution hazard [95% CI], 1.62 [1.06-2.47])., Conclusions: C/EI of beta-lactams in cirrhotic patients with BSI may improve outcomes and facilitate earlier discharge., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Infective endocarditis (IE) due to group A β-hemolytic streptococcus (Streptococcus pyogenes) has rarely been reported in the literature. We herein report a Streptococcus pyogenes native mitral valve endocarditis in a young patient and a review of the literature. The patient had a native mitral valve endocarditis with vegetation; his hemodynamic stability and a short course of antibiotic treatment prevented urgent surgery on the mitral valve. He was previously treated with cefixime and azithromycin for four days and then, upon hospital admission, with vancomycin plus amoxicillin-clavulanate. After the diagnosis of IE due to Streptococcus pyogenes, treatment with gentamicin (3 mg/kg daily) and ampicillin (12 g/day) was implemented. The patient underwent weekly echocardiographic evaluations during antibiotic treatment to document the resolution of the vegetations. He was discharged to home in good clinical conditions after a four-week course of antibiotic treatment., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance., Methods: Cirrhotic patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model., Results: We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure-SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29-18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93-5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28-1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73-4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48-4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12-0.73; p 0.008)., Conclusions: MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients., (Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Sepsis begins outside of the hospital for nearly 80% of patients and the emergency room (ER) represents the first contact with the health care system. This study evaluates a project to improve collection of blood cultures (BCs) in patients with sepsis in the ER consisting of staff education and completion of the appropriate BC pre-analytical phase. A retrospective observational study performed to analyse the data on BC collection in the ER before and after a three-phase project. The first phase (1 January to 30 June 2015) before the intervention consisted of evaluation of data on BCs routinely collected in the ER. The second phase (1 July to 31 December 2015) was the intervention phase in which educational courses on sepsis recognition and on pre-analytical phase procedures (including direct incubation) were provided to ER staff. The third phase (1 January to 30 June 2016; after the intervention) again consisted of evaluation. Before the intervention, out of 24,738 admissions to the ER, 103 patients (0.4%) were identified as septic and had BCs drawn (359 BC bottles); 19 out of 103 patients (18.4%) had positive BCs. After the intervention, out of 24,702 admissions, 313 patients (1.3%) had BCs drawn (1,242 bottles); of these, 96 (30.7%) had positive BCs. Comparing the first and third periods, an increase in the percentage of patients with BCs collected (from 0.4% to 1.3% respectively, p < 0.0001) and an increase in the percentages of patients with true-positive BCs (from 0.08% to 0.39% of all patients evaluated respectively, p < 0.0001) were observed. The isolation of bacteria by BCs increased 3.25-fold after project implementation. These results can be principally ascribed to an improved awareness of sepsis in the staff associated with improved pre-analytical phase procedures in BC collection.

This study investigated the epidemiology of tuberculosis in the last 16 years in the province of Pavia, Lombardy, Northern Italy. The objective was to evaluate the clinical pattern of tuberculosis in immigrant groups compared with Italians in an observational retrospective study conducted from 1998 to 2013. In all, 615 tuberculosis cases were admitted, 354 males (57.3%), median age 47-years, 425 (69.1%) Italian-born patients, 190 (30.9%) immigrants. The ratio between the immigrant group and the Italian-born group of patients increased from 1.7% to 54.5% in the study period (p=0.001). HIV was the most common comorbidity, affecting 48 patients (7.8%), followed by diabetes in 35 (5.7%) and COPD in 30 (4.9%). The overall admission-associated mortality was 5.5%. Italian-born patients were older than non-Italian born subjects and had at least one comorbidity, 162 (38.1%) and 22 (11.6%), respectively (p<0,0001). Mortality was increased among Italian-born compared with non-Italian-born patients (7.3% versus 1.6%, p=0.004). No significant variation in extra-pulmonary tuberculosis (EPTB) prevalence occurred. Considering specific form of EPTB, HIV infection was associated with an increased risk of EPTB (RR 2.02, 95%CI 1.09-3.74, p=0.026). There was a high risk of tuberculosis among immigrants, whereas a decreasing trend was consistently observed among Italian-born patients. Italian-born patients show a higher tuberculosis-associated mortality risk due to older age and comorbidities.

Few data have been published regarding the epidemiology and outcome of infective endocarditis (IE) in patients with chronic hepatic disease (CHD). A retrospective analysis of the Studio Endocarditi Italiano (SEI) database was performed to evaluate the epidemiology and outcome of CHD+ patients compared with CHD- patients. The diagnosis of IE was defined in accordance with the modified Duke criteria. Echocardiography, diagnosis, and treatment procedures were in accordance with current clinical practice. Among the 1722 observed episodes of IE, 300 (17.4 %) occurred in CHD+ patients. The cause of CHD mainly consisted of chronic viral infection. Staphylococcus aureus was the most common bacterial species in CHD+ patients; the frequency of other bacterial species (S. epidermidis, streptococci, and enterococci) were comparable among the two groups. The percentage of patients undergoing surgery for IE was 38.9 in CHD+ patients versus 43.7 in CHD- patients (p = 0.06). Complications were more common among CHD+ patients (77 % versus 65.3 %, p < 0.001); embolization (43.3 % versus 26.1 %, p < 0.001) and congestive heart failure (42 % versus 34.1 %, p = 0.01) were more frequent among CHD+ patients. Mortality was comparable (12.5 % in CHD- and 15 % in CHD+ patients). At multivariable analysis, factors associated with hospital-associated mortality were having an infection sustained by S. aureus, a prosthetic valve, diabetes and a neoplasia, and CHD. Being an intravenous drug user (IVDU) was a protective factor and was associated with a reduced death risk. CHD is a factor worsening the prognosis in patients with IE, in particular in patients for whom cardiac surgery was required.

Observational retrospective study to evaluate the etiology, the outcome and the risk factors of bloodstream infections (BSIs) in patients with liver disease. One hundred and forty-eight BSIs were diagnosed (infection rate: 0.60 per 100 days of hospital stay), 62 BSIs (41.9 %) were associated with Gram-positive bacteria (infection rate: 0.25 per 100 days of hospital stay) and 80 (54.4 %) with Gram-negative bacteria (infection rate: 0.32 per 100 days of hospital stay). Admission-associated mortality was higher in patients with BSI than in those without BSI (20.6 versus 5.0 %, p < 0.001). Patients with cirrhosis had an increased risk to develop a BSI compared with patients with chronic hepatitis, specifically for Gram-positive (and Staphylococcus spp)-related BSI.