Rethinking Combination Therapy for S. aureus bacteremia: A Fading Paradigm.

Staphylococcus aureus bacteremia presents clinical complexities, with prolonged duration associated with unfavorable outcomes. This research delves into unconventional treatments, such as combinations involving daptomycin, oxacillin, ceftaroline, and fosfomycin, with the aim of swiftly sterilizing bloodstream infection to reduce complications. Our examination of 30 MSSA bacteremia patients with infective endocarditis uncovers differing results between single-agent therapies (oxacillin or daptomycin) and combined treatment plans. Microbiologic clearance at the 72 hour mark demonstrates greater efficacy within the combination cohort (bacteremia persistence 29%) versus monotherapy (bacteremia persistence 78%). This limited case series suggests the potential superiority of combination therapy, prompting further investigations.

Time is running out. No excuses to delay implementation of antimicrobial stewardship programmes: impact, sustainability, resilience and efficiency through an interrupted time series analysis (2017-2022).

Introduction: The WHO declared antimicrobial resistance (AMR) a significant concern in 2014, sparking initiatives to ensure responsible antibiotic use. In human medicine, Antimicrobial Stewardship Programmes (ASPs) in hospitals play a pivotal role in combating AMR. Although evidence supports the effectiveness of ASPs in optimizing antimicrobial use, often the lack of resources becomes an excuse to limit their dissemination and use. This paper provides a comprehensive report on a 6-year analysis of an ASP implemented in a healthcare region in north-east Italy. Methods: A retrospective data collection was conducted to assess the programme's impact on antibiotic consumption expressed as DDDs/100 patient-days, its sustainability over time, resilience during the COVID-19 pandemic and the efficiency of the ASP (relationship between workload and human resources). Results: A substantial overall reduction in antibiotic consumption (-14%), particularly in fluoroquinolones (-64%) and carbapenems (-68%), was demonstrated, showcasing the programme's impact. Sustainability was confirmed through enduring trends in antibiotic consumption and ecological analysis over time. The ASP demonstrates resilience by maintaining positive trends even amid the challenging COVID-19 pandemic. Efficiency was underscored by an increase in on-site consultations despite consistent human resources until 2021. Conclusions: This study offers insights into the prolonged success of a resource-efficient ASP, emphasizing the crucial role of long-term commitment in fostering responsible antibiotic use in the context of global health challenges such as AMR.

The Management of Recurrent Urinary Tract Infection: Non-Antibiotic Bundle Treatment.

Recurrent urinary tract infections (rUTIs) are a common condition with high morbidity and negatively impact the quality of life. They account for approximately 25% of all antibiotic prescriptions and are a public health concern in an era of increasing multidrug-resistant organisms (MDROs). Several non-antibiotic treatment strategies have been tried to curb antimicrobial use, and many are effective to some degree, but no experience testing multimodal interventions. We created a "care bundle" consisting of behavioral interventions, vaginal and oral probiotics, D-mannose, and cranberry to be followed for six months. We enrolled women with rUTIs over three years. Changes in urinary tract infections, antibiotic use, chronic symptoms, and quality of life were compared in the six months before and after participation in the study. Forty-seven women were enrolled in the study, six of whom were excluded from the final analysis. We observed a 76% reduction in urinary tract infections (p < 0.001) and a reduction in total antibiotic exposure of more than 90% (p < 0.001); all chronic symptoms showed a trend toward reduction. Adherence to the bundle was high (87.2%). Overall, 80.5% of women experienced an improvement in their quality of life. In our experience, a bundle protocol is effective in reducing recurrences and antimicrobial use in a cohort of women with rUTIs and results in a subjective improvement in chronic symptoms and quality of life. Further research with larger sample size is needed to confirm these findings.

Dalbavancin in catheter-related bloodstream infections: a pilot study.

Background: Catheter-related bloodstream infections (CRBSI) represent a frequent complication of vascular catheterization, with high morbidity, mortality, and associated costs. Most infections are caused by Gram-positive bacteria; thus dalbavancin, a new long-acting lipoglicopeptide, may have a role in early patient discharge strategies optimizing treatment and reducing overall costs. Methods: In this small pilot feasibility study, we assessed the efficacy and safety of a "single step" treatment strategy combining dalbavancin administration (1500 mg IV single dose), catheter removal, and early discharge in adult patients admitted to medical wards in a three-year period. Results: We enrolled sixteen patients with confirmed Gram-positive CRBSI, with a mean age of 68 years and relevant comorbidities (median Charlson Comorbidity index=7). The most frequent causative agents were staphylococci, with 25% of methicillin-resistant strains, and the majority of infected devices were short term central venous catheter (CVC) and peripherally inserted central catheter (PICC). Ten out of sixteen patients had been treated empirically before dalbavancin administration. The mean time from dalbavancin administration to discharge was 2 days; none of the patients had adverse drug-related reactions; at 30- and 90-day follow-up, no patients have been readmitted to the hospital due to bacteraemia recurrence. Conclusions: Our results indicate that single-dose dalbavancin is highly effective, well-tolerated, and cost-saving for Gram-positive CRBSI.

Mortality predictors in hospitalised COVID-19 patients and the role of anti-SARS-CoV-2 IgG antibodies and remdesivir.

Background: In a pre-vaccination era serologic tests may be used to evaluate the seroprevalence and efficacy of containment strategies applied to the community. Subsequently, SARS-CoV-2 vaccination has successfully reduced hospitalization and admission to intensive care. The role of antiviral treatment for COVID-19 remains debated. Objective: We investigated the effect of SARS-CoV-2 IgG Spike (S) antibody responses in hospitalized patients on 30-day mortality. Finally, we assessed whether other predictive factors affected mortality after 30 days. Methods: Observational study on COVID-19 patients admitted from October 1, 2021, to January 30, 2022. Results: 520 patients were studied; 108 died at the 30-day follow-up (21%). A borderline significance for mortality was observed in favour of the high antibody titer group (24% vs 17%, p=0.05). From the univariate Cox regression analysis, a high IgG-S titer was significantly correlated to lower 30-day mortality (p=0.04, HR: 0.7; 95%CI: 0.44-0.98). The administration of remdesivir (p=0.01) and the age <65 years (p=2.3e-05) were found to be protective for the considered outcome (respectively, HR: 0.5, 95%CI: 0.34-0.86, and HR: 0.1, 95%CI: 0.04-0.30). Conclusions: S-antibodies and remdesivir could play a protecting role in increasing the survival of hospitalized COVID-19 patients who are not suffering from a critical disease. Advanced age is a risk factor for poor outcomes among infected people.

Multiple Bayesian network meta-analyses to establish therapeutic algorithms for metastatic triple negative breast cancer.

Metastatic triple-negative breast cancer (mTNBC) is a poor prognostic disease with limited treatments and uncertain therapeutic algorithms. We performed a systematic review and multiple Bayesian network meta-analyses according to treatment line to establish an optimal therapeutic sequencing strategy for this lethal disease. We included 125 first-line trials (37,812 patients) and 33 s/further-lines trials (11,321 patients). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rates (ORR), overall survival (OS) and safety, for first and further lines, separately. We also estimated separate treatment rankings for the first and subsequent lines according to each endpoint, based on (surface under the cumulative ranking curve) SUCRA values. No first-line treatment was associated with superior PFS and OS than paclitaxel ± bevacizumab. Platinum-based polychemotherapies were generally superior in terms of ORR, at the cost of higher toxicity.. PARP-inhibitors in germline-BRCA1/2-mutant patients, and immunotherapy + chemotherapy in PD-L1-positive mTNBC, performed similar to paclitaxel ± bevacizumab. In PD-L1-positive mTNBC, pembrolizumab + chemotherapy was better than atezolizumab + nab-paclitaxel in terms of OS according to SUCRA values. In second/further-lines, sacituzumab govitecan outperformed all other treatments on all endpoints, followed by PARP-inhibitors in germline-BRCA1/2-mutant tumors. Trastuzumab deruxtecan in HER2-low mTNBC performed similarly and was the best advanced-line treatment in terms of PFS and OS after sacituzumab govitecan, according to SUCRA values. Moreover, comparisons with sacituzumab govitecan, talazoparib and olaparib were not statistically significant. The most effective alternatives or candidates for subsequent lines were represented by nab-paclitaxel (in ORR), capecitabine (in PFS) and eribulin (in PFS and OS).

Home management of COVID-19 symptomatic patients: a safety study on COVID committed home medical teams.

To reduce the overburden in the hospital, during the COVID-19 pandemic, some "COVID Committed Home Medical Teams" (CCHTs) were created in Italy. These units consist of a small pool of general practitioners who aim to evaluate all patients with COVID-19 who require a medical examination directly at home. After the first visit (which can end with patient hospitalisation or home management), CCHTs periodically monitor the patients' clinical conditions and vital signs (usually a revaluation every 24-48 hours, except for a sudden worsening). However, this strategy - which reduces the pressure on hospitals - has never been evaluated for patient safety. Our study aims to determine whether a home-based monitoring and treatment strategy for non-severe COVID-19 patients was safe as direct hospital admission by the emergency department. We conducted a retrospective observational study about 1,182 patients admitted to the hospital for COVID-19 between September 2020 and April 2021, confronting in-hospital and 30-day mortality in both CCHT-referred (n=275) and directly admitted by emergency department (n=907). Patients assessed by the CCHT had lower in-hospital and 30-day mortality (18% vs 28%, p=0.001; and 20% vs 30%, p=0.002); but, in the propensity score matching comparison, there was no characteristic between the two groups turned out significantly different. CCHT did not correlate with in-hospital or 30-day mortality. CCHT is a safe strategy to reduce hospital overburden for COVID-19 during pandemic surges.

Antimicrobial Stewardship in the Covid-19 Pandemic.

During COVID-19 pandemic, implementing and maintaining an antimicrobial stewardship protocol obtained both low rates of MDR microorganisms and low antimicrobial use in an 800-bed hospital network in northern Italy. Infectious diseases specialist consulting was crucial to maintain this protocol active.

Rapidly progressive ischemic strokes and transient antiphospholipid syndrome during a mild SARS-CoV-2 infection.

SARS-CoV-2 infection is associated with an increased risk of thrombotic events, especially during severe forms of disease. Here we describe the clinical history of a patient with a mild form of Covid-19 infection presenting with multiple cerebral ischemic lesions that evolved in an atypical way.

Epidemiology of respiratory virus before and during COVID-19 pandemic.

The COVID pandemic has forcefully turned the spotlight on the importance of the diagnosis of respiratory virus infections. Viruses have always been a frequent and common cause of respiratory tract infections. Rapid molecular diagnostics applied to the diagnostics of respiratory virus infections has revolutionized microbiology laboratories only a few years ago. Few studies illustrate the epidemiology of respiratory viruses, and fewer still those that have compared the pre-pandemic to the pandemic period. During the first year of the pandemic (2020-2021) it was clear to everyone to witness a sudden disappearance of the circulation of all the other respiratory viruses, especially those typically isolated during the winter time, such as RSV and Influenza virus. In our study we wanted to verify this phenomenon and to study the epidemiology of our local reality, analyzing three consecutive flu seasons (2018-2019, 2019-2020, 2020-2021). The results lead us to note that the prevalence of positivity to respiratory virus infections went from 49.8% (2018-2019) and 39% (2019-2020) to 13.4% (2020-2021). This decrease is at least partly attributable to the security measures adopted (social distancing and mask), but it certainly opens up new scenarios when the restriction measures will be terminated. We believe such studies can provide real-world evidence of the effectiveness of public health interventions implemented during current and future pandemics.

Development and Validation of the Acute PNeumonia Early Assessment Score for Safely Discharging Low-Risk SARS-CoV-2-Infected Patients from the Emergency Department.

A continuous demand for assistance and an overcrowded emergency department (ED) require early and safe discharge of low-risk severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. We developed (n = 128) and validated (n = 330) the acute PNeumonia early assessment (aPNea) score in a tertiary hospital and preliminarily tested the score on an external secondary hospital (n = 97). The score's performance was compared to that of the National Early Warning Score 2 (NEWS2). The composite outcome of either death or oral intubation within 30 days from admission occurred in 101 and 28 patients in the two hospitals, respectively. The area under the receiver operating characteristic (AUROC) curve of the aPNea model was 0.86 (95% confidence interval (CI), 0.78-0.93) and 0.79 (95% CI, 0.73-0.89) for the development and validation cohorts, respectively. The aPNea score discriminated low-risk patients better than NEWS2 at a 10% outcome probability, corresponding to five cut-off points and one cut-off point, respectively. aPNea's cut-off reduced the number of unnecessary hospitalizations without missing outcomes by 27% (95% CI, 9-41) in the validation cohort. NEWS2 was not significant. In the external cohort, aPNea's cut-off had 93% sensitivity (95% CI, 83-102) and a 94% negative predictive value (95% CI, 87-102). In conclusion, the aPNea score appears to be appropriate for discharging low-risk SARS-CoV-2-infected patients from the ED.

Anthracyclines Strike Back: Rediscovering Non-Pegylated Liposomal Doxorubicin in Current Therapeutic Scenarios of Breast Cancer.

Anthracyclines are among the most active chemotherapies (CT) in breast cancer (BC). However, cardiotoxicity is a risk and peculiar side effect that has been limiting their use in clinical practice, especially after the introduction of taxanes. Non-pegylated liposomal doxorubicin (NPLD) has been developed to optimize the toxicity profile induced by anthracyclines, while maintaining its unquestionable therapeutic index, thanks to its delivering characteristics that increase its diffusion in tumor tissues and reduce it in normal tissues. This feature allows NPLD to be safely administered beyond the standard doxorubicin maximum cumulative dose of 450-480 mg/m2. Following three pivotal first-line phase III trials in HER2-negative metastatic BC (MBC), this drug was finally approved in combination with cyclophosphamide in this specific setting. Given the increasing complexity of the therapeutic scenario of HER2-negative MBC, we have carefully revised the most updated literature on the topic and dissected the potential role of NPLD in the evolving therapeutic algorithms.

Acute kidney injury and single-dose administration of aminoglycoside in the Emergency Department: a comparison through propensity score matching.

Purpose: According to the Surviving Sepsis Campaign, aminoglycosides (AG) can be administered together with a ß-lactam in patients with septic shock. Some authors propose administering a single dose of an AG combined with a ß-lactam antibiotic in septic patients to extend the spectrum of antibiotic therapy. The aim of this study has been to investigate whether a single shot of AG when septic patients present at the Emergency Department (ED) is associated with acute kidney injury (AKI). Methods: We retrospectively enrolled patients based on a 3-year internal registry of septic patients visited in the Emergency Department (ED) of Pordenone Hospital. We compared the patients treated with a single dose of gentamicin (in addition to the ß-lactam) and those who had not been treated to verify AKI incidence. Results: 355 patients were enrolled. The median age was 71 years (IQR 60-78). Less than 1% of the patients had a chronic renal disease. The most frequent infection source was the urinary tract (31%), followed by intra-abdominal and lower respiratory tract infections (15% for both). 131 patients received gentamicin. Unmatched data showed a significant difference between the two groups in AKI (79/131, 60.3% versus 102/224, 45.5%; p=0.010) and in infectious disease specialist's consultation (77/131, 59% versus 93/224, 41.5%; p=0.002). However, after propensity score matching, no significant difference was found. Conclusion: Our experience shows that a single-shot administration of gentamicin upon admission to the ED does not determine an increased incidence of AKI in septic patients.

Peritoneal Tuberculosis during Infliximab Treatment in a Patient with Ulcerative Colitis Despite a Negative Quantiferon Test.

Infliximab is an IgG1 antitumor necrosis factor monoclonal antibody that is commonly used to treat inflammatory bowel disease (IBD) and other autoimmune disorders. However, it is known to increase the risk of reactivation of latent tuberculosis (LTBI) due to its capability to disrupt TB granulomas. We describe a case of extrapulmonary TB in a patient with ulcerative colitis who was treated with Infliximab after a negative Quantiferon Test. In addition, we report briefly on the current controversy about the appropriateness, interval, and methods for the repeated screening of latent TB in IBD patients that are treated with antitumor necrosis factor alpha (TNF-α) antibodies.

Artificial neural network model from a case series of COVID-19 patients: a prognostic analysis.

BACKGROUND AND AIM: There is a need to determine which clinical variables predict the severity of COVID-19. We analyzed a series of critically ill COVID-19 patients to see if any of our dataset's clinical variables were associated with patient outcomes. METHODS: We retrospectively analyzed the data of COVID-19 patients admitted to the ICU of the Hospital in Pordenone from March 11, 2020, to April 17, 2020. Patients' characteristics of survivors and deceased groups were compared. The variables with a different distribution between the two groups were implemented in a generalized linear regression model (LM) and in an Artificial Neural Network (NN) model to verify the "robustness" of the association with mortality. RESULTS: In the considered period, we reviewed the data of 22 consecutive patients: 8 died. The causes of death were a severe respiratory failure (3), multi-organ failure (1), septic shock (1), pulmonary thromboembolism (2), severe hemorrhage (1). Lymphocyte and the platelet count were significantly lower in the group of deceased patients (p-value 0.043 and 0.020, respectively; cut-off values: 660/mm3; 280,000/mm3, respectively). Prothrombin time showed a statistically significant trend (p-value= 0.065; cut-off point: 16.8/sec). The LM model (AIC= 19.032), compared to the NN model (Mean Absolute Error, MAE = 0.02), was substantially alike (MSE 0.159 vs. 0.136). CONCLUSIONS: In the context of critically ill COVID-19 patients admitted to ICU, lymphocytopenia, thrombocytopenia, and lengthening of prothrombin time were strictly correlated with higher mortality. Additional clinical data are needed to be able to validate this prognostic score.

Endocrine-Based Treatments in Clinically-Relevant Subgroups of Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer: Systematic Review and Meta-Analysis.

A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26-41% and 12-27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60-0.65 vs. HR range for single agent ET: 0.59-1.37; OS HR range for combinations: 0.74-0.87 vs. HR range for single agent ET: 0.68-0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making.

Diagnostic performance of an automated chemiluminescence immunoassay for SARS-CoV-2 IgG and IgM antibodies detection: A real life experience.

BACKGROUND: Recently many serological assays for detection of antibodies to SARS-COV-2 virus were introduced on the market. Aim of this study was to assess the diagnostic performance of an automated CLIA for quantitative detection of anti-SARS-CoV-2 IgM and IgG antibodies. METHODS: A total of 354 sera, 89 from consecutive patients diagnosed with COVID-19 (43 mild, 32 severe and 13 critical) and 265 from asymptomatic and negative on rRT-PCR testing healthcare workers, were evaluated for IgM and IgG anti-SARS-CoV-2 antibodies with MAGLUMI immunoassay. RESULTS: The overall sensitivity and specificity were 86.5% (95%CI: 77.6-92.8) and 98.5% (95%CI:96.2-99.6), respectively. PPV, PPN, LR+, LR- and OR were 95.1 (95%CI: 87.8-98.6), 95.6 (95%CI: 92.4-97.7), 57.3 (95%CI: 21.6-152.1), 7.3 (95%CI: 4.31-12.4) and 418.6 (95%CI: 131.2-1335.2), respectively. The levels of SARS-CoV-2 IgM and IgG antibodies were 1.22 â€‹± â€‹1.2 AU/mL and 15.86 â€‹± â€‹24.83 AU/mL, 2.86 â€‹± â€‹2.4 AU/mL and 69.3 â€‹± â€‹55.5 AU/mL, 2.47 â€‹± â€‹1.33 AU/mL and 83.9 â€‹± â€‹83.9 AU/mL in mild, severe and critical COVID-19 groups, respectively. A significant difference in antibody levels between mild and severe/critical subjects has been shown. CONCLUSIONS: The CLIA assay showed good diagnostic performance and a significant association between antibody levels and severity of the disease was found.

Classification and analysis of outcome predictors in non-critically ill COVID-19 patients.

BACKGROUND: Early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients who could develop a severe form of COVID-19 must be considered of great importance to carry out adequate care and optimise the use of limited resources. AIMS: To use several machine learning classification models to analyse a series of non-critically ill COVID-19 patients admitted to a general medicine ward to verify if any clinical variables recorded could predict the clinical outcome. METHODS: We retrospectively analysed non-critically ill patients with COVID-19 admitted to the general ward of the hospital in Pordenone from 1 March 2020 to 30 April 2020. Patients' characteristics were compared based on clinical outcomes. Through several machine learning classification models, some predictors for clinical outcome were detected. RESULTS: In the considered period, we analysed 176 consecutive patients admitted: 119 (67.6%) were discharged, 35 (19.9%) dead and 22 (12.5%) were transferred to intensive care unit. The most accurate models were a random forest model (M2) and a conditional inference tree model (M5) (accuracy = 0.79; 95% confidence interval 0.64-0.90, for both). For M2, glomerular filtration rate and creatinine were the most accurate predictors for the outcome, followed by age and fraction-inspired oxygen. For M5, serum sodium, body temperature and arterial pressure of oxygen and inspiratory fraction of oxygen ratio were the most reliable predictors. CONCLUSIONS: In non-critically ill COVID-19 patients admitted to a medical ward, glomerular filtration rate, creatinine and serum sodium were promising predictors for the clinical outcome. Some factors not determined by COVID-19, such as age or dementia, influence clinical outcomes.

Canakinumab as treatment for COVID-19-related pneumonia: A prospective case-control study.

OBJECTIVES: Canakinumab is an IL-1ß antibody that neutralises the activity of IL-1ß. This study examined the efficacy and safety of canakinumab in patients with moderate COVID-19-related pneumonia. DESIGN: This study aimed to evaluate the reduction in duration of hospitalisation with adequate oxygen status. Forty-eight patients with moderate COVID-19-related pneumonia were asked to participate in the prospective case-control study: 33 patients (cases) signed informed consent and received canakinumab (Cohort 1) and 15 patients (Controls) refused to receive the experimental drug and received institutional standard of care (Cohort 2). RESULTS: Hospital discharge within 21 days was seen in 63% of patients in Cohort 1 vs. 0% in Cohort 2 (median 14 vs. 26 days, respectively; p < 0.001). There was significant clinical improvement in ventilation regimes following administration of canakinumab compared with Cohort 2 (Stuart-Maxwell test for paired data, p < 0.001). Patients treated with canakinumab experienced a significant increase in PaO2:FiO2 (p < 0.001) and reduction in lung damage by CT (p = 0.01), along with significant decreases in immune/inflammation markers that were not observed in Cohort 2. Only mild side-effects were seen in patients treated with canakinumab; survival at 60 days was 90.0% (95% CI 71.9-96.7) in patients treated with canakinumab and 73.3% (95% CI 43.6-89.1) for Cohort 2. CONCLUSIONS: Treatment with canakinumab in patients with COVID-19-related pneumonia rapidly restored normal oxygen status, decreased the need for invasive mechanical ventilation, and was associated with earlier hospital discharge and favourable prognosis versus standard of care.