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Background: In recent years, many aspects of the physiological role of PCSK9 have been elucidated, in particular regarding its role in lipid metabolism, cardiovascular risk but also its role in innate immunity. Increasing evidence is available on the involvement of PCSK9 in the pathogenesis of viral infections, mainly HCV, as well as in the regulation of host response to bacterial infections, mainly sepsis and septic shock. Moreover, the action of PCSK9 has been investigated as a crucial step in the pathogenesis of malaria infection and disease severity. Objective: Aim of this paper is to review available published literature on the role of PCSK9 in a wide array of infectious diseases. Conclusion: Besides the ongoing investigation on PCSK9 inhibition among HIV-infected patients for the treatment of HIV- and ART-related hyperlipidemia, preclinical studies indicate how PCSK9 is involved in reducing the replication of HCV. Moreover, a protective role of PCSK9 inhibition has also been proposed against dengue and SARS-CoV-2 viral infections. Interestingly, high plasmatic PCSK9 levels have been described in patients with sepsis. Finally, a loss of function in the PCSK9-encoding gene has been reported to possibly reduce mortality in malaria infection.

Background Severely immunocompromised patients are at risk for prolonged or relapsed Coronavirus Disease 2019 (COVID-19), leading to increased morbidity and mortality. We aimed to evaluate efficacy and safety of combination treatment in immunocompromised COVID-19 patients. Methods We included all immunocompromised patients with prolonged/relapsed COVID-19 treated with combination therapy with 2 antivirals (remdesivir plus nirmatrelvir/ritonavir, or molnupiravir in case of renal failure) plus, if available, anti-spike monoclonal antibodies (mAbs), between February and October 2022. The main outcomes were virological response at day 14 (negative Severe Acute Respiratory Syndrome Coronavirus 2 [SARS-CoV-2] swab) and virological and clinical response (alive, asymptomatic, with negative SARS-CoV-2 swab) at day 30 and the last follow-up. Results Overall, 22 patients (Omicron variant in 17/18) were included: 18 received full combination of 2 antivirals and mAbs and 4 received 2 antivirals only; in 20 of 22 (91%) patients, 2 antivirals were nirmatrelvir/ritonavir plus remdesivir. Nineteen (86%) patients had hematological malignancy, and 15 (68%) had received anti-CD20 therapy. All were symptomatic; 8 (36%) required oxygen. Four patients received a second course of combination treatment. The response rate at day 14, day 30, and last follow-up was 75% (15/20 evaluable), 73% (16/22), and 82% (18/22), respectively. Day 14 and 30 response rates were significantly higher when combination therapy included mAbs. Higher number of vaccine doses was associated with better final outcome. Two patients (9%) developed severe side effects (bradycardia leading to remdesivir discontinuation and myocardial infarction). Conclusions Combination therapy including 2 antivirals (mainly remdesivir and nirmatrelvir/ritonavir) and mAbs was associated with high rate of virological and clinical response in immunocompromised patients with prolonged/relapsed COVID-19.

Monkeypox (MPXV) usually causes a mild and self-limited infection. To date there are no data about cidofovir for the treatment for MPXV in humans. We report a case of a 25 years-old Brazilian man with a concurrent diagnosis of acute HIV (human immunodeficiency virus) infection, primary syphilis and MPXV infection with a nasal lesion successfully treated with intravenous cidofovir.

Background The objective of this study was to compare the clinical outcomes of patients receiving a short course (SC) vs a prolonged course (PC) of antifungal therapy for uncomplicated Candida bloodstream infections (BSIs). Methods All episodes of uncomplicated Candida BSI from September 1, 2018, to August 31, 2020, were reviewed. We compared the primary (all-cause 90-day mortality) and secondary study end points (1-year recurrent Candida BSI and all-cause 1-year mortality) among patients who underwent SC (5–11 days) or PC (12–24 days) therapy using propensity score analysis with the inverse probability of treatment weighting (IPTW) method. Results A total of 114 patients with uncomplicated Candida BSI were included: 35 (30.7%) were classified into the SC group (median [interquartile range {IQR}], 9 [7–11] days) and 79 (69.3%) into the PC group (median [IQR], 14 [14–16] days). Patients in the SC group compared with the PC group had a higher rate of hospitalization in the surgical ward (40.0% vs 19.0%; P = .02) or septic shock at the time of Candida BSI onset (11.4% vs 1.3%; P = .03). The risk of 90-day mortality was not different between the SC and PC groups (n = 8 [22.9%] vs 17 [21.5%], respectively; IPTW-adjusted subdistribution hazard ratio [sHR], 0.67; 95% CI, 0.31–1.47; P = .20). The risk for recurrent Candida BSI within 1 year of completing therapy (IPTW-adjusted sHR, 1.07; 95% CI, 0.20–5.80; P = .94) or for all-cause 1-year mortality (IPTW-adjusted HR, 0.72; 95% CI, 0.35–1.50; P = .38) did not differ between groups. Conclusions Receiving a short vs prolonged course of antifungal therapy did not affect mortality or BSI recurrence in patients with uncomplicated candidemia.

Background Antimicrobial resistance (AMR) among Gram Negative (GN) bacteria is a medical and economic concern. In the pediatric setting there is a paucity AMR data due to a lower surveillance in this population. Aim of this study is to describe incidence and outcomes of GN bloodstream infections (GN-BSI), especially caused by MDR among children admitted to intensive care unit of Istituto Giannina Gaslini Pediatric Hospital in Genoa from January 2017 to December 2021. Methods In this retrospective observational single-center study all pediatric patients admitted to ICU with GN-BSI were enrolled. We collected demographical and clinical data (such as underlying disease, empiric and targeted therapy, presence of devices, prior colonization due to MDR GN, prior treatments and surgery), and outcome and mortality at 7 and 30 days. Results Overall, 97 GN-BSI among 85 children admitted to PICU were included during the study period. Among all patients 40% (34/85) were male, with median age of 3 months (IQR: 1; 11; range: 0-292) and 75% (64/85) were aged < 1 years). Rates of GN BSI according to 1000 admission are showed in figure 1. The major causative agent was Klebsiella pneumoniae (28/97, 29%), followed by Escherichia coli (18/97, 18%), while 10 episodes (10%) were due to Pseudomonas aeruginosa (figure 2). A mechanism of resistance was found in 22/97 (23%), with a prevalence of ESBL producers (13/22, 59%), followed by AmpC (4/22, 18%) and KPC (2/22, 1%). 14/97 patients (14%) had a surveillance swab positive by the same bacteria causing BSI. The susceptibility to the 4 more used drugs for 4 more frequent pathogens are showed in figure 3. In 40% of GN-BSI the empiric therapy was piperacillin/tazobactam, followed by carbapenem in 28/98, 28% of episodes. Overall, 18 (21%) patients died, half of whom within 7 days of the BSI, including 3/6 of the onco/hematological patients. Figure 1Rates of GN BSI in PICU according to 1000 admissionFigure 2Species distributionFigure 3Susceptibility to the more used drugs for the more frequent pathogens. Conclusion This study confirmed the increasing role of GN in BSI and high mortality among children admitted to PICU, especially the youngest, with an increased rate in our Center. Carbapenem resistance isn’t common, but the empirical treatment with piperacillin/tazobactam often it might be useless. Disclosures All Authors: No reported disclosures.

Background Clinical trial demonstrated that SARS-CoV-2 vaccines have the ability of reduce mortality and morbidity due to COVID-19. The aim of this study is to describe the effect of vaccination in term of mortality, type of ventilation and ICU admission among patients hospitalized for COVID-19 from May to December 2021 in a Ligurian Hospital. Methods This is a retrospective, single-center study conducted in San Martino Hospital (Genoa, Italy), including patients ≥ 18 years hospitalized for COVID-19 in Infectious Disease and Emergency Units from 1st May to 31st December 2021. We collected demographical data, multimorbidity and disability score, vaccination time (“vaccinated” all patients hospitalized ≥ 14 days after first dose or ≥ 7 days after second/third dose), therapy for COVID-19, mortality at 7 and 30 days, ICU admission, ventilation type. Characteristics of vaccinated (group A) versus non vaccinated (group B) patients were compared using Chi-squared/Fisher's exact test for categorical variables and t-test /Kruskal-Wallis test for the continuous ones. Cox proportional hazards models for death at 30 days were performed as univariate analysis as well as adjusting for age, Cumulative Illness Rating Scale [CIRS], gender, Remdesivir, Monoclonal antibodies, Tocilizumab use. Results Overall, 405 patients SARS-CoV-2 infected were enrolled. Data about timing of vaccination were available for 360 patients (89%). We compared clinical characteristics and outcomes of group A (32%) versus group B (68%). In group A patients were older (p< 0.001) and frailer (higher CIRS score and lower Barthel index, p< 0.001) than in group B. Among patients requiring oxygen, 76 (31.5%) in group B vs 26 (22.41%) in group A needed high flow ventilation (p=0.036); 33 (13.52%) vs 3 (2.59%) respectively were admitted to ICU (Figure 1). Mortality at 30 days after hospitalization was higher in group A at univariate analysis [HR(95%CI) 1.44(0.82; 2.53), p=0.208], lower at multivariate analysis [0.57(0.31; 1.02), p=0.059]. Conclusion The results of this study confirm that SARS-CoV-2 vaccination reduces rate of admission to ICU and 30 days mortality among patients hospitalized for COVID-19. In our cohort mortality among vaccinated patients remains high and we hypothesized this is due to high frailty of evaluated population. Disclosures Chiara Dentone, CD, Angelini: Advisor/Consultant|Gilead: Advisor/Consultant|Menarini: Advisor/Consultant|Novartis: Advisor/Consultant Matteo Bassetti, PhD, Angelini: Advisor/Consultant|Astellas: Grant/Research Support|Bayer: Advisor/Consultant|Bayer: Honoraria|BioMe ́ rieux: Advisor/Consultant|BioMe ́ rieux: Honoraria|Cidara: Advisor/Consultant|Cidara: Honoraria|Cipla: Advisor/Consultant|Cipla: Honoraria|Gilead: Advisor/Consultant|Gilead: Honoraria|Menarini: Advisor/Consultant|Menarini: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Nabriva: Advisor/Consultant|Pfizer: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|Tetraphase: Advisor/Consultant.

To discuss empirical therapy for severe infections due to Gram-negative bacteria with difficult-to-treat resistance (GNB-DTR) in current clinical practice, focusing in particular on the positioning of novel therapeutic agents and rapid diagnostic tests.The current era of novel agents active against GNB-DTR and showing differential activity against specific determinants of resistance is an unprecedented scenario, in which the clinical reasoning leading to the choice of the empirical therapy for treating severe GNB-DTR infections is becoming more complex, but it also allows for enhanced treatment precision.Novel agents should be used in line with antimicrobial stewardship principles, aimed at reducing selective pressure for antimicrobial resistance. However, this does not mean that they should not be used. Indeed, excesses in restrictive uses may be unethical by precluding access to the most effective and less toxic treatments for patients with severe GNB-DTR infections. Given these premises (the 'how'), empirical treatment with novel agents should be considered in all patients with risk factors for GNB-DTR and severe clinical presentation of acute infection (the 'when'). Furthermore, empirical novel agents should preferably be continued only for a few hours, until de-escalation, modification, or confirmation (as targeted therapy) is made possible by the results of rapid diagnostic tests (the 'how long').

Background The risk of barotrauma associated with different types of ventilatory support is unclear in COVID- 19 patients. The primary aim of this study was to evaluate the effect of the different respiratory support strategies on barotrauma occurrence; we also sought to determine the frequency of barotrauma and the clinical characteristics of the patients who experienced this complication. Methods This multicentre retrospective case-control study from 1 March 2020 to 28 February 2021 included COVID-19 patients who experienced barotrauma during hospital stay. They were matched with controls in a 1:1 ratio for the same admission period in the same ward of treatment. Univariable and multivariable logistic regression (OR) were performed to explore which factors were associated with barotrauma and in-hospital death. Results We included 200 cases and 200 controls. Invasive mechanical ventilation was used in 39.3% of patients in the barotrauma group, and in 20.1% of controls (p

Purpose of review To summarize the available results of primary analyses from high-quality randomized studies of either recently approved or possible future agents for the treatment of acute bacterial skin and skin structure infections (ABSSSI). Recent findings In the last 2 decades, several novel agents have been approved for the treatment of ABSSSI, that are also active against methicillin-resistant Staphylococcus aureus (MRSA). In addition to already available agents, further molecules are in clinical development that could become available for treating ABSSSI in the forthcoming future. Summary The current and future availability of several new-generation antibiotics will allow to modulate therapeutic choices not only on efficacy but also on other relevant factors such as the combination of the drug safety profile and the comorbidities of any given patient, the expected adherence to outpatient therapy, and the possibilities of early discharge or avoiding hospitalization by means of oral formulations, early switch from intravenous to oral therapy, or single-dose administration of long-acting intravenous agents. With the advent of new-generation antibiotics, all these factors are becoming increasingly essential for tailoring treatment to individual patients in line with the principles of personalized medicine, and for optimizing the use of healthcare resources.

Background An unexpected high prevalence of enterococcal bloodstream infection (BSI) has been observed in critically ill patients with COVID-19 in the intensive care unit (ICU). Materials and methods The primary objective was to describe the characteristics of ICU-acquired enterococcal BSI in critically ill patients with COVID-19. A secondary objective was to exploratorily assess the predictors of 30-day mortality in critically ill COVID-19 patients with ICU-acquired enterococcal BSI. Results During the study period, 223 patients with COVID-19 were admitted to COVID-19-dedicated ICUs in our centre. Overall, 51 episodes of enterococcal BSI, occurring in 43 patients, were registered. 29 (56.9%) and 22 (43.1%) BSI were caused by Enterococcus faecalis and Enterococcus faecium, respectively. The cumulative incidence of ICU-acquired enterococcal BSI was of 229 episodes per 1000 ICU admissions (95% mid-p confidence interval [CI] 172–298). Most patients received an empirical therapy with at least one agent showing in vitro activity against the blood isolate (38/43, 88%). The crude 30-day mortality was 42% (18/43) and 57% (4/7) in the entire series and in patients with vancomycin-resistant E. faecium BSI, respectively. The sequential organ failure assessment (SOFA) score showed an independent association with increased mortality (odds ratio 1.32 per one-point increase, with 95% confidence interval 1.04–1.66, p = .021). Conclusions The cumulative incidence of enterococcal BSI is high in critically ill patients with COVID-19. Our results suggest a crucial role of the severity of the acute clinical conditions, to which both the underlying viral pneumonia and the enterococcal BSI may contribute, in majorly influencing the outcome.KEY MESSAGESThe cumulative incidence of enterococcal BSI is high in critically ill patients with COVID-19.The crude 30-day mortality of enterococcal BSI in critically ill patients with COVID-19 may be higher than 40%.There could be a crucial role of the severity of the acute clinical conditions, to which both the underlying viral pneumonia and the enterococcal BSI may contribute, in majorly influencing the outcome.

The possible negative impact of severe adult respiratory distress caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19) on antimicrobial stewardship and infection control has been postulated, but few real-life data are available. The aim of this study was to report our experience with colonization/infection of carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Candida auris among critically ill COVID-19 patients admitted to the intensive care unit (ICU). All COVID-19 patients admitted to the ICUs at San Martino Policlinico Hospital&ndash, IRCCS in Genoa, Italy, were screened from 28 February to 31 May 2020. One-hundred and eighteen patients admitted to COVID-19 ICUs were included in the study. Among them, 12 (10.2%) became colonized/infected with CRPA, 6 (5.1%) with C. auris and 2 (1.6%) with CR-Kp. All patients with CRPA received prior treatment with meropenem, and in 11 (91.7%) infection was not preceded by colonization. Four patients (66.7%) developed C. auris candidemia. A significant spread of resistant pathogens was observed among critically ill COVID-19 patients. Dedicated strategies are warranted to prevent horizontal spread and maintain effective antimicrobial stewardship programs in the setting of COVID-19 care.

Treatment of severe infections due to Acinetobacter baumannii with difficult-to-treat resistance (DTR-AB), which exhibits resistance to all β-lactams, β-lactam/β-lactamases inhibitor combinations, ...

PURPOSE OF REVIEW To discuss the currently available evidence about the use oritavancin and dalbavancin for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and for other potential indications. RECENT FINDINGS In this review, we briefly summarize the available data on efficacy (from randomized controlled trials) and on effectiveness and cure rates (from observational studies) pertaining to the use of oritavancin and dalbavancin either for ABSSSI or for other indications. SUMMARY Oritavancin and dalbavancin are valid options for outpatient therapy and early discharge in patients with ABSSSI, especially when adherence to oral therapy cannot be guaranteed or no oral choices are available. Furthermore, it is worth noting that a non-negligible portion (sometimes the majority) of oritavancin and dalbavancin use in available real-life experiences is for indications other than ABSSSI, especially for Gram-positive osteomyelitis and endocarditis. The number of studies on the use of long-acting lipoglycopeptides for these currently off-label indications is rapidly increasing and will help to further optimize the use of these peculiar antibiotics in the forthcoming future.

The possible negative impact of severe adult respiratory distress caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19) on antimicrobial stewardship and infection control has been postulated, but few real-life data are available. The aim of this study was to report our experience with colonization/infection of carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Klebsiella pneumoniae (CR-Kp) and Candida auris among critically ill COVID-19 patients admitted to the intensive care unit (ICU). All COVID-19 patients admitted to the ICUs at San Martino Policlinico Hospital–IRCCS in Genoa, Italy, were screened from 28 February to 31 May 2020. One-hundred and eighteen patients admitted to COVID-19 ICUs were included in the study. Among them, 12 (10.2%) became colonized/infected with CRPA, 6 (5.1%) with C. auris and 2 (1.6%) with CR-Kp. All patients with CRPA received prior treatment with meropenem, and in 11 (91.7%) infection was not preceded by colonization. Four patients (66.7%) developed C. auris candidemia. A significant spread of resistant pathogens was observed among critically ill COVID-19 patients. Dedicated strategies are warranted to prevent horizontal spread and maintain effective antimicrobial stewardship programs in the setting of COVID-19 care.

Treatment of severe infections due toThe present perspective provides a personal view on both current and future agents for the treatment of severe DTR-AB infections.We currently are in a transition era for the treatment of DTR-AB infections, where in the past 20 years, polymyxin-based regimens have become the most used approach (although possibly suboptimal, there were few or no alternatives) and where in the next 20 years, polymyxins will likely be replaced by less toxic novel agents as first-line choices. Two novel antimicrobial agents have been recently approved that show activity against DTR-AB, cefiderocol and eravacycline, while durlobactam/sulbactam is in phase-3 of clinical development. In the near future, these agents could become important first-line choices for the treatment of DTR-AB within approved indications, or for off-label indications in the absence of dependable alternatives. Good-quality post-marketing experiences remain necessary for arising clinically relevant questions and guiding the design of further dedicated randomized controlled trials to stably optimize the use of novel agents for DTR-AB infections in the next decades.

IntroductionCoronavirus disease 2019 (COVID-19) can lead to respiratory failure due to severe immune response. Treatment targeting this immune response might be beneficial but there is limited evidence on its efficacy.The aim of this study was to determine if early treatment of patients with COVID-19 pneumonia with tocilizumab and/or steroids was associated with better outcome.MethodsThis observational single-center study included patients with COVID-19 pneumonia who were not intubated and received either standard of care (SOC, controls) or SOC plus early (within 3 days from hospital admission) anti-inflammatory treatment. SOC consisted of hydroxychloroquine 400mg bid plus, in those admitted before March 24th, also darunavir/ritonavir. Anti-inflammatory treatment consisted of either tocilizumab (8mg/kg intravenously or 162mg subcutaneously) or methylprednisolone 1 mg/kg for 5 days or both. Failure was defined as intubation or death, and the endpoints were failure-free survival (primary endpoint) and overall survival (secondary) at day 30. Difference between the groups was estimated as Hazard Ratio by a propensity score weighted Cox regression analysis (HROW).ResultsOverall, 196 adults were included in the analyses. They were mainly male (67.4%), with comorbidities (78.1%) and severe COVID-19 pneumonia (83.7%). Median age was 67.9 years (range, 30-100) and median PaO2/FiO2200 mmHg (IQR 133-289). Among them, 130 received early anti-inflammatory treatment with: tocilizumab (n=29, 22.3%), methylprednisolone (n=45, 34.6%), or both (n=56, 43.1%). The adjusted failure-free survival among tocilizumab/methylprednisolone/SOC treated patients vs. SOC was 80.8% (95%CI, 72.8-86.7) vs. 64.1% (95%CI, 51.3-74.0), HROW0.48, 95%CI, 0.23-0.99; p=0.049. The overall survival among tocilizumab/methylprednisolone/SOC patients vs. SOC was 85.9% (95%CI, 80.7-92.6) vs. 71.9% (95%CI, 46-73), HROW0.41, 95%CI: 0.19-0.89, p=0.025.ConclusionEarly adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia.

Objectives To describe clinical characteristics, management and outcome of individuals with coronavirus disease 2019 (COVID-19); and to evaluate risk factors for all-cause in-hospital mortality. Methods This retrospective study from a University tertiary care hospital in northern Italy, included hospitalized adult patients with a diagnosis of COVID-19 between 25 February 2020 and 25 March 2020. Results Overall, 317 individuals were enrolled. Their median age was 71 years and 67.2% were male (213/317). The most common underlying diseases were hypertension (149/317; 47.0%), cardiovascular disease (63/317; 19.9%) and diabetes (49/317; 15.5%). Common symptoms at the time of COVID-19 diagnosis included fever (285/317; 89.9%), shortness of breath (167/317; 52.7%) and dry cough (156/317; 49.2%). An ‘atypical' presentation including at least one among mental confusion, diarrhoea or nausea and vomiting was observed in 53/317 patients (16.7%). Hypokalaemia occurred in 25.8% (78/302) and 18.5% (56/303) had acute kidney injury. During hospitalization, 111/317 patients (35.0%) received non-invasive respiratory support, 65/317 (20.5%) were admitted to the intensive care unit (ICU) and 60/317 (18.5%) required invasive mechanical ventilation. All-cause in-hospital mortality, assessed in 275 patients, was 43.6% (120/275). On multivariable analysis, age (per-year increase OR 1.07; 95% CI 1.04–1.10; p Conclusions COVID-19 mainly affected elderly patients with predisposing conditions and caused severe illness, frequently requiring non-invasive respiratory support or ICU admission. Despite supportive care, COVID-19 remains associated with a substantial risk of all-cause in-hospital mortality.