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New therapies and vaccines changed the management of COVID-19. The aim of this retrospective study was to describe characteristics, in-hospital mortality and its predictors in patients with moderate/severe COVID-19, considering the 4 different pandemic waves and viral variants' prevalence from February 2020 to January 2022. Among 1135 patients included, 873 (77%) had at least one comorbidity, 177 (16%) were immunocompromised. From waves 1 to 4, patients with severe respiratory failure and ICU admission decreased over time ( p  < 0.001), like the length of in-hospital stay ( p  < 0.001). Despite a reduction of in-hospital mortality from 19% to 11%, increased risk of death was related to older age and immunocompromising conditions, especially during the 4th wave (HR = 5.07 and HR = 10.86, p  < 0.001 respectively) while remdesivir treatment in the 3rd wave (HR = 0.41, p  = 0.010) and positive serology (aHR = 0.66, p  = 0.027) were protective for survival. These data support the need for tailoring vaccine campaign for future COVID-19 waves.

Objectives: The serum (1,3)-beta-d-glucan (BDG) assay gives quicker results and has higher sensitivity than blood cultures, therefore it is advised for early diagnosis of invasive candidemia and/or discontinuation of empirical therapy. Its sensitivity may depend on different factors. The aim of our study was to analyse the in vitro and in vivo BDG levels in clinical isolates of three species of Candida responsible for candidemia., Methods: C. albicans, C. parapsilosis, and C. auris strains were collected from blood cultures of patients who had a concurrent (-1 to +3 days) serum BDG test (Fungitell assay). Supernatants of all strains were tested in quadruplicate for BDG levels., Results: Twenty-two C. auris, 14 C. albicans, and ten C. parapsilosis strains were included. The median BDG levels in supernatants were 463 pg/mL (interquartile range [IQR] 379-648) for C. auris, 1080 pg/mL (IQR 830-1276) for C. albicans, and 755 pg/mL (IQR 511-930) for C. parapsilosis, with the significant difference among the species (p < 0.0001). Median serum BDG levels (IQR) were significantly lower in case C. auris and C. parapsilosis vs. C. albicans (p < 0.0001), respectively, 50 pg/mL (IQR 15-161) and 57 pg/mL (IQR 18-332), vs. 372 pg/mL (IQR 102-520). Sensitivity of serum BDG was 39% (95% confidence interval [CI], 18-64) in case of C. auris, 30% (95% CI, 8-65) C. parapsilosis and 78% (95% CI, 49-94) C. albicans candidemia., Discussion: In our centre C. auris and C. parapsilosis strains have lower BDG content as compared with C. albicans, with a potential impact on serum BDG performance for the diagnosis of candidemia., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Isavuconazole is first-line treatment of invasive aspergillosis. Therapeutic drug monitoring (TDM) is deemed not necessary, since most patients reached therapeutic levels (>1 mg/L) in large studies. Low levels were reported in some critically ill patients admitted to the ICU. The aim was to compare isavuconazole levels between critically ill and non-critically ill patients., Materials and Methods: Retrospective analysis of data from all patients treated with standard-dose isavuconazole between 1 January 2019 and 26 October 2022 was performed. The following data were collected: TDM results from the first 30 days of therapy; ward of admission; demographic and clinical characteristics; continuous renal replacement therapy; extracorporeal membrane oxygenation; and co-administered drugs., Results: Seventy-two patients (median age 65 years) and 188 TDM measurements (mean number of samples per patient 2.6 ± 1.7) were included; 33 (45.8%) were ICU patients (3 also had haematological disorders); 39 (54.2%) were non-ICU patients, of whom 31 had haematological disorders. In all patients, the mean isavuconazole blood level was 3.33 ± 2.26 mg/L. Significantly lower levels were observed in the ICU versus the non-ICU population: mean 2.02 ± 1.22 versus 4.15 ± 2.31 mg/L (P < 0.001). Significantly higher rates of subtherapeutic levels were observed in ICU patients compared with the non-ICU population: all determinations <2 mg/L in 33.3% versus 7.7%, and all determinations <1 mg/L in 12.1% versus 0%, respectively. Predictors of lower isavuconazole levels were admission to the ICU, BMI > 25 kg/m2, bilirubin > 1.2 mg/dL and the absence of haematological disorder., Conclusions: ICU patients had significantly lower isavuconazole blood levels compared to non-ICU population. The TDM of isavuconazole for efficacy should be performed in ICU., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Despite advancements in health systems and intensive care unit (ICU) care, along with the introduction of novel antibiotics and microbiologic techniques, mortality rates in severe community-acquired pneumonia (sCAP) patients have not shown significant improvement. Delayed admission to the ICU is a major risk factor for higher mortality. Apart from choosing the appropriate site of care, prompt and appropriate antibiotic therapy significantly affects the prognosis of sCAP. Treatment regimens involving ceftaroline or ceftobiprole are currently considered the best options for managing patients with sCAP. Additionally, several other molecules, such as delafloxacin, lefamulin, and omadacycline, hold promise as therapeutic strategies for sCAP. This review aims to provide a comprehensive summary of the key challenges in managing adults with severe CAP, focusing on essential aspects related to antibiotic treatment and investigating potential strategies to enhance clinical outcomes in sCAP patients., Competing Interests: Outside the submitted work, M.B. reports research grants and/or advisor/consultant and/or speaker/chairman fees from Bayer, BioMerieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, Shionogi, and Tillotts Pharma. Outside the submitted work, D.R.G. reports investigator-initiated grants from Pfizer, Shionogi, and Gilead Italia, and speaker and/or advisory board fees from Pfizer and Tillotts Pharma. Outside of the submitted word A.V. reports research grants and/or advisor/consultant and/or speaker/chairman fees from Gilead, Menarini, MSD, Pfizer, Tillotts Pharma, and Shionogi. The other authors have no conflicts of interest to declare., (Thieme. All rights reserved.)

Candida auris outbreaks are increasingly frequent worldwide. In our 1000-bed hospital, an endemic transmission of C. auris was established in two of five intensive care units (ICUs). Aims of our study were to describe the occurrence of new cases of C. auris colonization and infection outside the endemic ICUs, in order to add evidence for future policies on screening in patients discharged as negative from an endemic setting, as well as to propose a new algorithm for screening of such high-risk patients. From 26 March 2021 to 26 January 2023, among 392 patients who were diagnosed as colonized or infected with C. auris in our hospital, 84 (21.4%) received the first diagnosis of colonization or infection outside the endemic ICUs. A total of 68 patients out of 84 (81.0%) had a history of prior admission to the endemic ICUs. All were screened and tested negative during their ICU stay with a median time from last screening to discharge of 3 days. In 57/68 (83.8%) of patients, C. auris was detected through screening performed after ICU discharge, and 90% had C. auris colonization detected within 9 days from ICU discharge. In 13 cases (13/57 screened, 22.8%), the first post-ICU discharge screening was negative. In those not screened, candidemia was the most frequent event of the first C. auris detection (6/11 patients not screened). In settings where the transmission of C. auris is limited to certain wards, we suggest screening both at discharge from the endemic ward(s) even in case of a recent negative result, and at least twice after admission to nonendemic settings.

To achieve the World Health Organization goal of hepatitis C virus (HCV) eradication, barriers to treatment should be investigated and overcome. The aim of this study was to identify those barriers and describe the strategies adopted to achieve HCV micro-elimination in a cohort of coinfected people living with HIV (PLWH-HCV). Adult PLWH-HCV followed at our hospital with detectable serum HCV-RNA in 2018 were enrolled. After a three-year follow-up, barriers to HCV treatment were investigated and strategies to overcome them were described. Of 492 PLWH-HCV seen in 2018, 29 (5.9%) had detectable serum HCV-RNA. Eight out of 29 (27.6%) were excluded because they were already under treatment, while 2 others were excluded because they moved to other outpatient clinics. Among the remaining 19 study participants, the most common barriers to treatment were poor adherence to therapies and follow-up visits (n=9, 47%), recent HCV diagnosis awaiting proper staging (n=3, 16%) and treatment hesitancy (n=2, 10%). During the following three years, direct-acting antivirals (DAAs) treatment was completed in 11/19 (58%) cases, with achievement of sustained virological response in 100% of cases. For the remaining cases, 2/19 (10.5%) were lost to follow-up, 2/19 (10.5%) died before treatment initiation and 4/19 (21.0%) are still awaiting treatment. Despite 3 years of effort, HCV micro-elimination has not been achieved at our center. We observed that poor adherence and treatment hesitancy were the main barriers to treatment. Strategies addressing these issues need to be implemented.

Background: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic, life-threatening disease commonly affecting immunocompromised patients. The distribution of predisposing diseases or conditions in critically ill patients admitted to intensive care unit (ICU) and subjected to diagnostic work-up for PJP has seldom been explored., Materials and Methods: The primary objective of the study was to describe the characteristics of ICU patients subjected to diagnostic workup for PJP. The secondary objectives were: (i) to assess demographic and clinical variables associated with PJP; (ii) to assess the performance of Pneumocystis PCR on respiratory specimens and serum BDG for the diagnosis of PJP; (iii) to describe 30-day and 90-day mortality in the study population., Results: Overall, 600 patients were included in the study, of whom 115 had presumptive/proven PJP (19.2%). Only 8.8% of ICU patients subjected to diagnostic workup for PJP had HIV infection, whereas hematological malignancy, solid tumor, inflammatory diseases, and solid organ transplants were present in 23.2%, 16.2%, 15.5%, and 10.0% of tested patients, respectively. In multivariable analysis, AIDS (odds ratio [OR] 3.31; 95% confidence interval [CI] 1.13-9.64, p = 0.029), non-Hodgkin lymphoma (OR 3.71; 95% CI 1.23-11.18, p = 0.020), vasculitis (OR 5.95; 95% CI 1.07-33.22, p = 0.042), metastatic solid tumor (OR 4.31; 95% CI 1.76-10.53, p = 0.001), and bilateral ground glass on CT scan (OR 2.19; 95% CI 1.01-4.78, p = 0.048) were associated with PJP, whereas an inverse association was observed for increasing lymphocyte cell count (OR 0.64; 95% CI 0.42-1.00, p = 0.049). For the diagnosis of PJP, higher positive predictive value (PPV) was observed when both respiratory Pneumocystis PCR and serum BDG were positive compared to individual assay positivity (72% for the combination vs. 63% for PCR and 39% for BDG). Cumulative 30-day mortality and 90-day mortality in patients with presumptive/proven PJP were 52% and 67%, respectively., Conclusion: PJP in critically ill patients admitted to ICU is nowadays most encountered in non-HIV patients. Serum BDG when used in combination with respiratory Pneumocystis PCR could help improve the certainty of PJP diagnosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., Competing Interests: Potential conflicts of interest. E. A. reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Vertex Pharmaceuticals and Celgene (Bristol-Myers Squibb), Vifor Pharma, Novartis, Blue Bird Bio, Menarini Stemline, Glaxo, Regeneron, Gilead, and Novartis. M. B. reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Bayer, bioMérieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, and Shionogi. D. R. G. reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Gilead, Shionogi, Pfizer, and Tillotts Pharma. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Acute bacterial skin and skin-structure infections (ABSSSIs) are a common source of morbidity in both the community and hospital settings. The current standard of care (SoC) requires multiple-dose intravenous (IV) regimens, which are associated with high hospitalisation rates, concomitant event risks and costs. Dalbavancin is a lipoglycopeptide, long-acting antibiotic that is effective against Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). Dalbavancin allows treatment of ABSSSIs with a single-shot IV administration or once weekly for 2 weeks, enabling clinicians to treat patients in an outpatient setting or to shorten the length of hospital stay., Methods: This multicentre, observational, retrospective study compared hospitalised patients who received dalbavancin and patients treated with the three most used IV antibiotics of the same or similar class: vancomycin, teicoplanin and daptomycin. The primary outcome was the time to discharge after starting the study antibiotics., Results: The primary endpoint, time to discharge from the study therapy start, was measured for both groups: the median number of days was 6.5 in the dalbavancin group vs. 11.0 days in the SoC group. Moreover, in subpopulations of patients receiving one or more concomitant antibiotics active for Gram-positives, MRSA and patients with the most prevalent comorbidity (i.e., diabetes), the advantage of dalbavancin in terms of length of stay was confirmed, with a halved time to discharge or more. Safety data on dalbavancin were consistent with data collected in clinical trials. No serious adverse drug reactions related to dalbavancin were reported and most of them were classified as skin and subcutaneous tissue disorders. One serious ADR was reported for daptomycin., Conclusions: Although the analysis was only descriptive, it can be concluded that dalbavancin may enable a remarkable reduction in length of hospital stay, also confirming the clinical effectiveness and good safety profile demonstrated in clinical trials in a real-world setting., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A difficult-to-control outbreak of Candida auris is ongoing in a large tertiary care hospital in Liguria, Italy, where it first emerged in 2019. In a retrospective analysis, 503 cases of C. auris carriage or infection were observed between July 2019 and December 2022. Genomic surveillance identified putative cases that no longer occurred as part of one defined outbreak and the emergence of echinocandin (pandrug) resistance following independent selection of FKS1 S639F and FKS1 F635Y mutants upon prolonged exposure to caspofungin and/or anidulafungin.

Competing Interests: Outside the submitted work, MB reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from BioMérieux, Cidara, Gilead, Menarini, MSD, Pfizer, and Shionogi. Outside the submitted work, DG reports investigator-initiated grants from Pfizer, Shionogi, and Gilead Italia, and speaker and/or advisor fees from Pfizer and Tillotts Pharma. Outside the submitted work, AM reports investigator-initiated grant from Gilead Italia. Outside the submitted work, VDP reports research grant from Seegene Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Introduction: Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections represent a leading cause of purulent skin and soft tissue infections in some geographical regions. Traditionally, 'old antibiotics' such as trimethoprim-sulfamethoxazole, tetracyclines, clindamycin, chloramphenicol,vancomycin, and teicoplanin have been used to treat these infections, but these were often associated with low efficacy and excessive side effects and toxicity, especially nephrotoxicity. Along with the development of new compounds, the last decade has seen substantial improvements in the management of CA-MRSA infections., Areas Covered: In this review, the authors discuss the current and emerging drug treatment strategies to tackle invasive CA-MRSA infections. Articles reported in this review were selected from through literature searches using the PubMed database., Expert Opinion: The availability of new drugs showing a potent in vitro activity against CA-MRSA represents a unique opportunity to face the threat of resistance while potentially reducing toxicity. All these compounds represent promising options to enhance our antibiotic armamentarium. However, data regarding the use of these new drugs in real-life studies are limited and their best placement in therapy and in terms of optimization of medical resources and balance of cost-effectiveness requires further investigation.

The use of rapid molecular tests may anticipate the identification of causative agents and resistance determinants in the blood of critically ill patients with sepsis. From April to December 2021, all intensive care unit patients with sepsis or septic shock who were tested with the T2Bacteria and T2Resistance assays were included in a retrospective, single center study. The primary descriptive endpoints were results of rapid molecular tests and concomitant blood cultures. Overall, 38 combinations of T2Bacteria and T2Resistance tests were performed. One or more causative agent(s) were identified by the T2Bacteria assay in 26% of episodes (10/38), whereas negative and invalid results were obtained in 66% (25/38) and 8% (3/38) of episodes, respectively. The same pathogen detected by the T2Bacteria test grew from blood cultures in 30% of cases (3/10). One or more determinant(s) of resistance were identified by the T2Resistance assay in 11% of episodes (4/38). Changes in therapy based on T2Bacteria and/or T2Resistance results occurred in 21% of episodes (8/38). In conclusion, T2Bacteria/T2Resistance results can influence early treatment decisions in critically ill patients with sepsis or septic shock in real-life practice. Large, controlled studies remain necessary to confirm a favorable impact on patients' outcomes and antimicrobial stewardship interventions.

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., Competing Interests: Potential conflicts of interest. Outside the submitted work, D.R.G. reports investigator-initiated grants from Pfizer Inc., Shionogi, and Gilead Italia. Outside the submitted work, M.B. reports research grants and/or personal fees for advisor/consultant and/or speaker/chairman from Bayer, BioMérieux, Cidara, Cipla, Gilead, Menarini, MSD, Pfizer, and Shionogi. Outside the submitted work, A.V. has participated on advisory boards and/or received speaker fees from Angelini, Menarini, Merck Sharp and Dohme, Pfizer, and Shionogi. He has also received study grants from Merck Sharp and Dohme and Astellas. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We prospectively studied immunological response against SARS-CoV-2 after vaccination among healthcare workers without (group A) and with previous infection (group B). The analyses were collected at T0 (before the BNT162b2), T1 (before the second dose), T2 and T6 (1 and 6 months after the second dose). For cellular immune response, the activation-induced cell marker assay was performed with CD4 and CD8 Spike peptide megapools expressed as Stimulation Index. For humoral immune response, we determined antibodies to Spike-1 and nucleocapsid protein. The linear mixed model compared specific times to T0. The CD4+ Spike response overall rate of change was significant at T1 (p = 0.038) and at T2 (p < 0.001), while decreasing at T6. For CD8+ Spike reactivity, the interaction between the time and group was significant (p = 0.0265), and the p value for group comparison was significant at the baseline (p = 0.0030) with higher SI in previously infected subjects. Overall, the anti-S Abs significantly increased from T1 to T6 compared to T0. The group B at T6 retained high anti-S titer (p < 0.001). At T6, in both groups we found a persistent humoral response and a high CD4+ T cell response able to cross recognize SARS-COV-2 variants including epsilon, even if not a circulating virus at that time.

Serum beta-D-glucan (BDG) determination plays an important role in the diagnosis of candidemia among critically ill patients admitted to the intensive care unit (ICU). However, BDG levels measured may be lower in the case of infections caused by some non- albicans species, such as C. parapsilosis and C. auris . The aim of this single-center study was to investigate the sensitivity of serum BDG for the diagnosis of candidemia stratified according to causative Candida species in ICU patients. This was a single-center, retrospective study, including all adult patients admitted to ICU during the period 2018-2021. All episodes of candidemia with a determination of BDG available within 3 days before or after positive blood culture were recorded. The preplanned primary objective was to investigate the sensitivity of serum BDG to detect candidemia early and the effect of different Candida species. The secondary objective was to measure serum BDG in patients with candidemia from different Candida species. In total, 146 candidemia episodes in 118 patients were analyzed. Median BDG value for C. albicans candidemia (182 pg/mL) was higher than that observed for C. parapsilosis (78 pg/mL, p = 0.015) and C. auris (48 pg/mL, p = 0.022). The overall sensitivity of BDG for the diagnosis of candidemia was low (47%, 95% CI 39-55%). In conclusion, in critically ill patients admitted to ICU, serum BDG levels for candidemia were different among species, with lower levels confirmed for C. parapsilosis and C. auris . Serum BDG sensitivity for early detection of candidemia was lower than previously reported in other ICU populations.

Rapid start of antiretroviral therapy (ART) pending genotypic resistance test (GRT) has been recently proposed, but the effectiveness of this strategy is still debated. The rate of virological success (VS), defined as HIV-RNA < 50 copies/ml, with and without GRT was compared in drug-naïve individuals enrolled in the Italian ARCA cohort who started ART between 2015 and 2018. 521 individuals started ART: 397 without GRT (pre-GRT group) and 124 following GRT (post-GRT group). Overall, 398 (76%) were males and 30 (6%) were diagnosed with AIDS. In the pre-GRT group, baseline CD4+ cell counts were lower (p < 0.001), and viral load was higher (p < 0.001) than in the post-GRT group. The estimated probability of VS in pre-GRT versus post-GRT group was 72.54% (CI 95 : 67.78-76.60) versus 66.94% (CI 95 : 57.53-74.26) at Week 24 and 92.40% (CI 95 : 89.26-94.62) versus 92.92% (CI 95 : 86.35-96.33) at Week 48, respectively (p = 0.434). At Week 48, VS was less frequent among individuals with baseline CD4+ cell counts <200 versus >500 (90.33% vs. 97.33%), log viral load <5.00 versus >5.70 log 10 cps/ml (97.17% vs 78.16%; p < 0.001), and those treated with protease inhibitors or non-nucleoside reverse transcriptase inhibitors versus those treated with integrase strand transfer inhibitors (p < 0.001). The rate of VS does not seem to be affected by an early ART initiation pending GRT results, but it could be influenced by the composition of the ART regimen, as well as immuno-virological parameters., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Objectives: Serum (1,3)-beta-d-glucan (BDG) assay is a non-culture-based test recommended for the diagnosis of invasive candidiasis owing to its faster results and higher sensitivity than blood cultures. Its performance might vary for different Candida species. The aim of this study was to determine in vitro levels of BDG in Candida auris culture supernatants and evaluate BDG levels in patients with C. auris candidemia sustained by these stains., Methods: C. auris strains were collected from blood cultures of patients who had a concomitant (-24 to +72 hours) serum BDG test (Fungitell assay). Supernatants of broth media culture of C. auris strains and two Candida albicans (controls) strains were prepared and tested for BDG., Results: Ten C auris strains were included. Supernatants of two C. albicans considered as controls had a mean BDG level of 1155 pg/mL (considered 100% reactivity). The median BDG level in supernatants of C. auris strains was 275 pg/mL (IQR 165-523 pg/mL), with a median reactivity of 24% (range 6%-72%). In vivo, the median BDG level was 129 pg/mL (IQR, 28-199 pg/mL). Sensitivity of BDG for C. auris candidemia was 60%. All patients received antifungal treatment with an echinocandin initiated a median of 2 days (IQR -8 to 0) before blood collection for BDG., Discussion: Our C. auris strains released lower amounts of BDG when compared to C. albicans. Clinical implications include lower sensitivity of serum BDG for the diagnosis of C. auris candidemia with a consequent impact on management protocols in settings with high prevalence of this species., (Copyright © 2022. Published by Elsevier Ltd.)

We sought to assess the characteristics and outcomes of neutropenic hematologic patients with Pseudomonas aeruginosa (PA) bloodstream infection (BSI) treated with ceftolozane-tazobactam (C/T). We conducted a multicenter, international, matched-cohort study of PA BSI episodes in neutropenic hematologic patients who received C/T. Controls were patients with PA BSI treated with other antibiotics. Risk factors for overall 7-day and 30-day case fatality rates were analyzed. We compared 44 cases with 88 controls. Overall, 91% of episodes were caused by multidrug-resistant (MDR) strains. An endogenous source was the most frequent BSI origin (35.6%), followed by pneumonia (25.8%). There were no significant differences in patient characteristics between groups. C/T was given empirically in 11 patients and as definitive therapy in 41 patients. Treatment with C/T was associated with less need for mechanical ventilation (13.6% versus 33.3%; P = 0.021) and reduced 7-day (6.8% versus 34.1%; P = 0.001) and 30-day (22.7% versus 48.9%; P = 0.005) mortality. In the multivariate analysis, pneumonia, profound neutropenia, and persistent BSI were independent risk factors for 30-day mortality, whereas lower mortality was found among patients treated with C/T (adjusted OR [aOR] of 0.19; confidence interval [CI] 95% of 0.07 to 0.55; P = 0.002). Therapy with C/T was associated with less need for mechanical ventilation and reduced 7-day and 30-day case fatality rates compared to alternative agents in neutropenic hematologic patients with PA BSI. IMPORTANCE Ceftolozane-tazobactam (C/T) has been shown to be a safe and effective alternative for the treatment of difficult to treat infections due to Pseudomonas aeruginosa (PA) in the general nonimmunocompromised population. However, the experience of this agent in immunosuppressed neutropenic patients is very limited. Our study is unique because it is focused on extremely immunosuppressed hematological patients with neutropenia and bloodstream infection (BSI) due to PA (mainly multidrug resistant [MDR]), a scenario which is often associated with very high mortality rates. In our study, we found that the use of C/T for the treatment of MDR PA BSI in hematological neutropenic patients was significantly associated with improved outcomes, and, in addition, it was found to be an independent risk factor associated with increased survival. To date, this is the largest series involving neutropenic hematologic patients with PA BSI treated with C/T.

Data on the long-term durability of rilpivirine (RPV) are still scarce. A two-center retrospective study was performed, including all people living with HIV (PLWH) treated with tenofovir disoproxil fumarate/emtricitabine (TDF/FTC)/RPV or tenofovir alafenamide (TAF)/FTC/RPV in the period January 2013-December 2019. Aims of the study were to assess the rate of discontinuation of the RPV single-tablet regimen (STR) and identify factors associated with the risk of discontinuation according to Cox's regression analysis. A total of 684 PLWH were enrolled. Mean duration of RPV-STR treatment was 192.5 (±99.5) weeks for 123 antiretroviral therapy (ART)-naïve participants (18%) and 173.3 (± 85.6) weeks for 561 ART-experienced study participants (82%). During the study period, the incidence of discontinuation was 7.7 per 100 person-years. The estimated proportions of discontinuation after 48 and 96 weeks were 5.6% and 13.4%, respectively. Causes of discontinuation were loss to follow-up (30%), side effects (15%), ART optimization (14%), virological failure (VF) (12%), death or transfer to another center (9%), low adherence (7%), drug interactions (6%), simplification to dual therapy (3%), and unknown (3%). No differences were observed in cumulative probability of discontinuation between ART-naïve and -experienced PLWH. Heterosexual (hazard ratio [HR] 3.0, 95% confidence interval [CI] 1.4-6.8) and mother-to-child (HR 5.3, 95% CI 1.8-15.3) transmission of HIV infection and history of previous VF (HR 1.7, 95% CI 1.2-2.5) were associated with higher risk of discontinuation. High RPV-STR effectiveness and durability were confirmed in our real-life population of PLWH. Given these data, RPV has the potential to be a drug for life in patients selected according to current guidelines.

Introduction: Candida auris (C. auris) is an emerging nosocomial pathogen, and a sharp rise in cases of colonization and infection has been registered in intensive care units (ICUs) during the ongoing coronavirus disease 2019 (COVID-19) pandemic. The unfavorable resistance profile of C. auris and the potential high mortality of C. auris infections represent an important challenge for physicians., Methods: We conducted a single-center retrospective study including all patients admitted to ICUs with isolation of C. auris in any non-sterile body site between February 20, 2020, and May 31, 2021. The primary aim of the study was to assess the cumulative incidence of C. auris candidemia in colonized patients. The secondary aim was to identify predictors of C. auris candidemia in the study population., Results: During the study period, 157 patients admitted to ICUs in our hospital became colonized with C. auris; 59% of them were affected by COVID-19. Overall, 27 patients (17%) developed C. auris candidemia. The cumulative risk of developing C. auris candidemia was > 25% at 60 days after first detection of C. auris colonization. Seven patients with C. auris candidemia (26%) also developed a late recurrent episode. All C. auris blood isolates during the first occurring episode were resistant to fluconazole and susceptible to echinocandins, while 15 (56%) were resistant to amphotericin B. During late recurrent episodes, emergent resistance to caspofungin and amphotericin B occurred in one case each. In the final multivariable model, only multisite colonization retained an independent association with the development of C. auris candidemia., Conclusion: Candida auris candidemia may occur in up to one fourth of colonized critically ill patients, and multisite colonization is an independent risk factor for the development of candidemia. Implementing adequate infection control measures remains crucial to prevent colonization with C. auris and indirectly the subsequent development of infection., (© 2022. The Author(s).)

Aim of this study was to assess the predictors of virological failure (VF) among patients living with HIV (PLWHIV) switching from an effective first-line antiretroviral therapy (ART) regimen, and to evaluate the emergence of resistance-associated mutations. All adult patients enrolled in the Antiviral Response Cohort Analysis cohort who started ART after 2010, with at least 6 months of virological suppression (VS) before ART switch and with an available genotypic resistance test (GRT) at baseline were included. Thirty-two patients out of the 607 PLWHIV included (5.3%) experienced VF after a median of 11 months from ART switch. Younger age (adjusted Hazard Ratio [aHR] 0.96, 95% confidence interval [CI] 0.92-0.99, p  = .023), being male who have sex with male (aHR 0.15, 95% CI 0.03-0.69, p  = .014), and longer time from VS to ART switch (aHR 0.97, 95% CI 0.95-1.00, p  = .021) resulted protective toward VF, while receiving a first-line regimen containing a backbone other than ABC/3TC or TXF/FTC (aHR 3.61, 95% CI 1.00-13.1, p  = .050) and a boosted protease inhibitor as anchor drug (aHR 3.34, 95% CI 1.20-9.28, p  = .021) were associated with higher risk of VF. GRT at the moment of VF was available only for 13 patients (40.6%). ART switch in patients with stable control of HIV infection is a safe practice, even if particular attention should be paid in certain cases of patients switching from regimens containing low-performance backbones or protease inhibitors.

Background: The diagnosis of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is challenging, and the role of Aspergillus-PCR in bronchoalveolar lavage (BAL) is unknown., Objectives: This study evaluated diagnostic accuracy of Aspergillus-PCR in BAL in IPA in three different cohorts: ICU-admitted patients with COVID-19, ICU-admitted patients without COVID-19 and immunocompromised patients., Methods: All stored available BAL samples collected from three patient groups were tested with Aspergillus-PCR (AsperGenius ® ). IPA was diagnosed according to appropriate criteria for each patient group., Results: We included 111 BAL samples from 101 patients: 52 (51%) patients admitted to ICU for COVID-19, 24 (24%) admitted to ICU for other reasons and 25 (25%) immunocompromised. There were 31 cases of IPA (28%). Aspergillus-PCR sensitivity was 64% (95% CI 47-79) and specificity 99% (95% CI 93-100). Aspergillus-PCR sensitivity was 40% (95%CI 19-64) in ICU COVID-19, 67% (95% CI 21-93) in non-COVID-19 ICU patients and 92% (95%CI 67-98) in the immunocompromised. The concordance between positive BAL-GM and BAL-PCR in patients with and without IPA was significantly lower in ICU patients (32%; 43% in COVID-19, 18% in non-COVID-19) than in the immunocompromised (92%), p < .001., Conclusions: Aspergillus-PCR in BAL improves the diagnostic accuracy of BAL-GM in ICU patients., (© 2022 Wiley-VCH GmbH.)

Purpose of Review: Some patients with coronavirus disease 2019 (COVID-19) may develop pulmonary bacterial coinfection or superinfection, that could unfavorably impact their prognosis., Recent Findings: The exact burden of methicillin-resistant Staphylococcus aureus (MRSA) lung infection in peculiar populations such as patients with COVID-19 remains somewhat elusive, possibly because of wide heterogeneity in methods and endpoints across studies., Summary: There was important heterogeneity in the retrieved literature on the epidemiology of MRSA lung infection in patients with COVID-19, both when considering all other bacteria as the denominator (relative prevalence ranging from 2% to 29%) and when considering only S. aureus as the denominator (relative prevalence ranging from 11% to 65%). Overall, MRSA is among the most frequent causative agents of pulmonary infection in patients with COVID-19. Improving our ability to rapidly reach etiological diagnosis of bacterial lung infection in COVID-19 patients remains fundamental if we are to improve the rates of appropriate antibiotic therapy in patients with COVID-19 and concomitant/superimposed MRSA infection, at the same time avoiding antibiotic overuse in line with antimicrobial stewardship principles., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Reactivation of herpes simplex virus type 1 (HSV-1) has been described in critically ill patients with coronavirus disease 2019 (COVID-19) pneumonia. In the present two-center retrospective experience, we primarily aimed to assess the cumulative risk of HSV-1 reactivation detected on bronchoalveolar fluid (BALF) samples in invasively ventilated COVID-19 patients with worsening respiratory function. The secondary objectives were the identification of predictors for HSV-1 reactivation and the assessment of its possible prognostic impact. Overall, 41 patients met the study inclusion criteria, and 12/41 patients developed HSV-1 reactivation (29%). No independent predictors of HSV-1 reactivation were identified in the present study. No association was found between HSV-1 reactivation and mortality. Eleven out of 12 patients with HSV-1 reactivation received antiviral therapy with intravenous acyclovir. In conclusion, HSV-1 reactivation is frequently detected in intubated patients with COVID-19. An antiviral treatment in COVID-19 patients with HSV-1 reactivation and worsening respiratory function might be considered.

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., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

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.

Objectives: The hypothesis of this study is that tocilizumab should affect common signs of infection due to its immunosuppressive properties. Primary aim of the study was to investigate whether the administration of tocilizumab to critically ill patients with COVID-19, led to a different clinical presentation of infectious complications compared to patients who did not receive tocilizumab. Secondary aim was investigating differences in laboratory parameters between groups., Methods: Single-centre retrospective study, enrolling COVID-19 patients who developed a microbiologically confirmed infectious complication [ventilator associated pneumonia or bloodstream infection] after intensive care unit [ICU] admission and either treated with tocilizumab or not [controls]., Results: A total of 58 patients were included, 25 treated with tocilizumab and 33 controls. Median time from tocilizumab administration to infection onset was 10 days [range 2-26]. Patients were 78% male, with median age 65 years [range 45-79]. At first clinical presentation of the infectious event, the frequency of hypotension [11/25, 44% vs. 11/33, 33%], fever [8/25, 32% vs. 10/33, 30%] or hypothermia [0/25,0%, vs. 2/33, 6%], and oxygen desaturation [6/25, 28% vs 4/33, 12%], as well as the frequency of SOFA score increase of ≥ 2 points [4/25, 16%,vs. 4/33, 12%] was similar in tocilizumab treated patients and controls [p>0.1 for all comparisons]. Among laboratory parameters, C-Reactive Protein elevation was reduced in tocilizumab treated patients compared to controls [8/25, 32% vs. 22/33, 67%, p=0.009]., Conclusion: The clinical features of infectious complications in critically ill patients with COVID-19 admitted to ICU were not affected by tocilizumab., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: Candida auris is responsible for hospital outbreaks worldwide. Some C. auris isolates may show concomitant resistance to azoles, echinocandins, and polyenes, thereby possibly leaving clinicians with few therapeutic options., Areas Covered: Antifungal agents both in early and in late phases of clinical development showing anti- C. auris activity., Expert Opinion: The research on antifungal agents active against C. auris has made important steps forward in recent years: ( i ) the development of drugs with novel mechanisms of action, such as ibrexafungerp and fosmanogepix, could provide a valid option against C. auris strains resistant to one or more older antifungals, including pan-resistant strains; ( ii ) rezafungin could allow once weekly administration of an active drug in the case of echinocandin-susceptible isolates, providing an effective outpatient treatment, while at the same time relieving selective pressure on novel classes; (iii) the development of oral formulations could allow step-down therapy and/or early discharge, or even to avoid hospitalization in mild or noninvasive diseases; ( iv ) according to available data, these novel agents show a good safety profile and a low potential for drug-drug interactions.

Background: The primary objective of the study is to describe the cellular characteristics of bronchoalveolar lavage fluid (BALF) of COVID-19 patients requiring invasive mechanical ventilation; the secondary outcome is to describe BALF findings between survivors vs non-survivors., Materials and Methods: Patients positive for SARS-CoV-2 RT PCR, admitted to ICU between March and April 2020 were enrolled. At ICU admission, BALF were analyzed by flow cytometry. Univariate, multivariate and Spearman correlation analyses were performed., Results: Sixty-four patients were enrolled, median age of 64 years (IQR 58-69). The majority cells in the BALF were neutrophils (70%, IQR 37.5-90.5) and macrophages (27%, IQR 7-49) while a minority were lymphocytes, 1%, TCD3+ 92% (IQR 82-95). The ICU mortality was 32.8%. Non-survivors had a significantly older age (p = 0.033) and peripheral lymphocytes (p = 0.012) were lower compared to the survivors. At multivariate analysis the percentage of macrophages in the BALF correlated with poor outcome (OR 1.336, CI95% 1.014-1.759, p = 0.039)., Conclusions: In critically ill patients, BALF cellularity is mainly composed of neutrophils and macrophages. The macrophages percentage in the BALF at ICU admittance correlated with higher ICU mortality. The lack of lymphocytes in BALF could partly explain a reduced anti-viral response.

Background: The goal of this study was to investigate the prevalence and factors associated with persistent viral shedding (PVS) in hospitalized patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection., Methods: This was a prospective observational study including all consecutive adults hospitalized with SARS-CoV-2 infection. When the first nasopharyngeal swab was positive for SARS-CoV-2 RNA (day 0), additional samples were obtained on days + 3, + 5, + 7 and then once every 7 days until virus detection was negative. PVS was defined as the duration of shedding of at least 21 days after diagnosis. The primary endpoint of this study was the prevalence of PVS., Results: Data were obtained regarding 121 consecutive hospitalized patients with SARS-CoV-2 infection (median age 66 years, male sex 65.3%). Overall, the prevalence of PVS was 38% (46/121 patients). According to univariate analysis, factors associated with PVS were immunosuppression (6.7% vs 21.7%, p = 0.02), increased interleukin-6 (IL-6) levels (≥ 35 ng/ml) at the time of diagnosis (43.4% vs 67.3%, p = 0.02), time from onset of symptoms to diagnosis (median days 7.0 vs 3.5, p = 0.001), intensive care unit admission (22.7% vs 43.5%, p = 0.02), and need for invasive mechanical ventilation (20.0% vs 41.3%, p = 0.01). The multivariate analysis indicated that immunosuppression, increased IL-6 levels at the time of diagnosis, time from onset of symptoms to diagnosis, and need for mechanical ventilation were independent factors associated with PVS., Conclusions: PVS was detected in up to 38% of hospitalized patients with SARS-CoV-2 infection and was strongly associated with immunosuppression, increased IL-6 levels, and the need for mechanical ventilation.

Candida auris is an emerging MDR pathogen raising major concerns worldwide. In Italy, it was first and only identified in July 2019 in our hospital (San Martino Hospital, Genoa), where infection or colonization cases have been increasingly recognized during the following months. To gain insights into the introduction, transmission dynamics, and resistance traits of this fungal pathogen, consecutive C. auris isolates collected from July 2019 to May 2020 ( n = 10) were subjected to whole-genome sequencing (WGS) and antifungal susceptibility testing (AST); patients' clinical and trace data were also collected. WGS resolved all isolates within the genetic clade I (South Asian) and showed that all but one were part of a cluster likely stemming from the index case. Phylogenetic molecular clock analyses predicted a recent introduction (May 2019) in the hospital setting and suggested that most transmissions were associated with a ward converted to a COVID-19-dedicated ICU during the pandemic. All isolates were resistant to amphotericin B, voriconazole, and fluconazole at high-level, owing to mutations in ERG11 (K143R) and TACB1 (A640V). Present data demonstrated that the introduction of MDR C. auris in Italy was a recent event and suggested that its spread could have been facilitated by the COVID-19 pandemic. Continued efforts to implement stringent infection prevention and control strategies are warranted to limit the spread of this emerging pathogen within the healthcare system.

The primary objective of this multicenter, observational, retrospective study was to assess the incidence rate of ventilator-associated pneumonia (VAP) in coronavirus disease 2019 (COVID-19) patients in intensive care units (ICU). The secondary objective was to assess predictors of 30-day case-fatality of VAP. From 15 February to 15 May 2020, 586 COVID-19 patients were admitted to the participating ICU. Of them, 171 developed VAP (29%) and were included in the study. The incidence rate of VAP was of 18 events per 1000 ventilator days (95% confidence intervals [CI] 16-21). Deep respiratory cultures were available and positive in 77/171 patients (45%). The most frequent organisms were Pseudomonas aeruginosa (27/77, 35%) and Staphylococcus aureus (18/77, 23%). The 30-day case-fatality of VAP was 46% (78/171). In multivariable analysis, septic shock at VAP onset (odds ratio [OR] 3.30, 95% CI 1.43-7.61, p = 0.005) and acute respiratory distress syndrome at VAP onset (OR 13.21, 95% CI 3.05-57.26, p < 0.001) were associated with fatality. In conclusion, VAP is frequent in critically ill COVID-19 patients. The related high fatality is likely the sum of the unfavorable prognostic impacts of the underlying viral and the superimposed bacterial diseases.

Background: The prevalence of kidney involvement during SARS-CoV-2 infection has been reported to be high. Nevertheless, data are lacking about the determinants of acute kidney injury (AKI) and the combined effect of chronic kidney disease (CKD) and AKI in COVID-19 patients., Methods: We collected data on patient demographics, comorbidities, chronic medications, vital signs, baseline laboratory test results and in-hospital treatment in patients with COVID-19 consecutively admitted to our Institution. Chronic kidney disease was defined as eGFR < 60 mL/min per 1.73 m 2 or proteinuria at urinalysis within 180 days prior to hospital admission. AKI was defined according to KDIGO criteria. The primary and secondary outcomes were the development of AKI and death., Results: Of 777 patients eligible for the study, acute kidney injury developed in 176 (22.6%). Of these, 79 (45%) showed an acute worsening of a preexisting CKD, and 21 (12%) required kidney replacement therapy. Independent associates of AKI were chronic kidney disease, C-reactive protein (CRP) and ventilation support. Among patients with acute kidney injury, 111 died (63%) and its occurrence increased the risk of death by 60% (HR 1.60 [95% IC 1.21-2.49] p = 0.002) independently of potential confounding factors including hypertension, preexisting kidney damage, and comorbidities. Patients with AKI showed a significantly higher rate of deaths attributed to bleeding compared to CKD and the whole population (7.5 vs 1.5 vs 3.5%, respectively)., Conclusion: Awareness of kidney function, both preexisting CKD and development of acute kidney injury, may help to identify those patients at increased risk of death.

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.

The aim of the present study is to evaluate if an independent association exists between liver enzyme elevations (LEE) and the risk of mortality or intensive care unit (ICU) admissions in patients with COVID-19. This was a single-center observational study, recruiting all consecutive adults with COVID-19. The elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) to the highest level between COVID-19 diagnosis and hospital discharge was categorized according to a standardized toxicity grade scale. In total, 799 patients were included in this study, 39% of which were female, with a mean age of 69.9 (±16.0) years. Of these patients, 225 (28.1%) developed LEE of grade ≥2 after a median of three days (interquartile range (IQR): 0-8 days) from the diagnosis of COVID-19, and they were estimated to have a higher hazard of death or ICU admission (adjusted hazard ratio (aHR): 1.46, 95% confidence interval (CI): 1.14-1.88). The clinical and laboratory variables associated with the development of LEE were male sex, higher respiratory rate, higher gamma glutamyl transpeptidase (GGT) and lower albumin levels at baseline. Among the analyzed treatments, steroids, tocilizumab and darunavir/ritonavir correlated with LEE. In conclusion, LEE were associated with mortality and ICU admission among COVID-19 patients. While the origin of LEE is probably multifactorial, LEE evaluation could add information to the clinical and laboratory variables that are commonly evaluated during the course of COVID-19.

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 < 0.001), cardiovascular disease (OR 2.58; 95% CI 1.07-6.25; p 0.03), and C-reactive protein levels (per-point increase OR 1.009; 95% CI 1.004-1.014; p 0.001) were independent risk factors for all-cause in-hospital mortality., 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., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Among people with perinatal HIV infection (PHIV), non-communicable diseases, such as chronic kidney disease, are increasing. Both HIV replication and antiretroviral therapy are recognised causes of renal impairment. Objective of the study is to describe the impact of viremia copy-years (VCY) and antiretroviral therapy on trend of estimated glomerular filtration rate (eGFR) in a cohort of adults with perinatal HIV infection. We conducted a multicentre observational study in sixty adults living with PHIV across a 9-year period, from January 2010 to December 2018. The mean values of eGFR were analysed at the first (T0) and last year of observation (T1). VCY was defined as the area under HIV-RNA curve during the study period. We analysed data according to antiretroviral therapy: tenofovir disoproxil (TDF), non-nucleoside reverse transcriptase inhibitors (NNRTI), boosted protease inhibitors (PI/b), integrase inhibitors (INI). We observed a mean overall eGFR reduction from 126.6 mL/min (95%CI: 119.6-133.5) to 105.0 mL/min (95%CI: 99.55-110.6) (p<0.001). Older age, higher baseline eGFR, higher VCY and longer exposure to INI treatment were associated with eGFR reduction at univariate analysis. In the multivariate model, older age (p = 0.039), baseline eGFR (p<0.001) and VCY (p = 0.069), were retained. We also observed a longer exposure to PI/b and INI in patients with lower control on HIV-RNA, expressed as VCY>2 log10. Our study outlines a progressive eGFR reduction in young adults with PHIV, related to the lower control on HIV-RNA VCY and related to aging., Competing Interests: NO authors have competing interests.

Background: Little is known about the incidence and risk of intensive care unit (ICU)-acquired bloodstream infections (BSI) in critically ill patients with coronavirus disease 2019 (COVID-19)., Materials and Methods: This retrospective, single-centre study was conducted in Northern Italy. The primary study objectives were as follows: (a) to assess the incidence rate of ICU-acquired BSI and (b) to assess the cumulative risk of developing ICU-acquired BSI., Results: Overall, 78 critically ill patients with COVID-19 were included in the study. Forty-five episodes of ICU-acquired BSI were registered in 31 patients, with an incidence rate of 47 episodes (95% confidence interval [CI] 35-63) per 1000 patient-days at risk. The estimated cumulative risk of developing at least one BSI episode was of almost 25% after 15 days at risk and possibly surpassing 50% after 30 days at risk. In multivariable analysis, anti-inflammatory treatment was independently associated with the development of BSI (cause-specific hazard ratio [csHR] 1.07 with 95% CI 0.38-3.04 for tocilizumab, csHR 3.95 with 95% CI 1.20-13.03 for methylprednisolone and csHR 10.69 with 95% CI 2.71-42.17 for methylprednisolone plus tocilizumab, with no anti-inflammatory treatment as the reference group; overall P for the dummy variable = 0.003)., Conclusions: The incidence rate of BSI was high, and the cumulative risk of developing BSI increased with ICU stay. Further study will clarify if the increased risk of BSI we detected in COVID-19 patients treated with anti-inflammatory drugs is outweighed by the benefits of reducing any possible pro-inflammatory dysregulation induced by SARS-CoV-2., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

We aimed to assess the prevalence of and factors associated with anti- severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) positivity in a large population of adult volunteers from five administrative departments of the Liguria and Lombardia regions. A total of 3609 individuals were included in this analysis. Participants were tested for anti-SARS-CoV-2 antibodies [Immunoglobulin G (IgG) and M (IgM) class antibodies] at three private laboratories (Istituto Diganostico Varelli, Medical Center, and Casa della Salute di Genova). Demographic data, occupational or private exposure to SARS-CoV-2-infected patients, and prior medical history consistent with SARS-CoV-2 infection were collected according to a preplanned analysis. The overall seroprevalence of anti-SARS-CoV-2 antibodies (IgG and/or IgM) was 11.0% [398/3609; confidence interval (CI) 10.0%-12.1%]. Seroprevalence was higher in female inmates than in male inmates (12.5% vs. 9.2%, respectively, p = 0.002), with the highest rate observed among adults aged >55 years (13.2%). A generalized estimating equations model showed that the main risk factors associated with SARS-CoV-2 seroprevalence were the following: an occupational exposure to the virus [Odd ratio (OR) = 2.36; 95% CI 1.59-3.50, p = 0.001], being a long-term care facility resident (OR = 4.53; 95% CI 3.19-6.45, p = 0.001), and reporting previous symptoms of influenza-like illness (OR = 4.86; 95% CI 3.75-6.30, p = 0.001) or loss of sense of smell or taste (OR = 41.00; 95% CI 18.94-88.71, p = 0.001). In conclusion, we found a high prevalence (11.0%) of SARS-CoV-2 infection that is significantly associated with residing in long-term care facilities or occupational exposure to the virus. These findings warrant further investigation into SARS-CoV-2 antibody prevalence among the Italian population.

Introduction: Coronavirus 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., Methods: This 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)., Results: Overall, 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/FiO2 200 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), HROW 0.48, 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), HROW 0.41, 95%CI: 0.19-0.89, p = 0.025., Conclusion: Early adjunctive treatment with tocilizumab, methylprednisolone or both may improve outcomes in non-intubated patients with COVID-19 pneumonia., Competing Interests: The authors have declared that no competing interests exist

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is among the most frequent causative agents of acute bacterial skin and skin-structure infections (ABSSSI) and has been associated with increased risks of invasive disease and of treatment failure., Areas Covered: In this review, we focus on those novel anti-MRSA agents currently in phase I or II of clinical development that may enrich the armamentarium against ABSSSI caused by MRSA in the future., Expert Opinion: Promising agents belonging to either old or novel antibiotic classes are currently in early phases of clinical development and may become available in the future for the effective treatment of ABSSSI caused by MRSA. In particular, the future availability of agents belonging to novel classes will be important for guaranteeing an effective treatment and for allowing outpatient treatment/early discharge, with a consequent reduced impact on healthcare resources. However, this does not mean that we can relax our efforts directed toward improving the responsible use of already available agents. Indeed, preserving their activity in the long term is crucial for optimizing the use of healthcare resources.

Purpose of Review: To summarize the available efficacy and safety data of novel agents for treating acute bacterial skin and skin-structure infections (ABSSSI), focusing on those active against methicillin-resistant Staphylococcus aureus (MRSA)., Recent Findings: There are now several agents active against MRSA that are approved for the treatment of ABSSSI, including tedizolid, ceftaroline, dalbavancin, telavancin, oritavancin, delafloxacin, and omadacycline. In addition, iclaprim has completed phase-3 randomized clinical trials (RCTs)., Summary: Considering the similar efficacy that arose from direct comparisons in phase-3 RCTs, in order to adopt the best approach for treating ABSSSI on patient-tailored basis, the different safety profiles and formulations of the different available agents should be balanced by taking into account the specific features of each treated patient in terms of baseline comorbidities, related risk of toxicity, need for hospitalization, possibility of early discharge, and expected adherence to outpatient oral therapy.

Background: It is still unclear what might be the best management of people living with HIV (PLWHIV) with low level viremia (LLV) despite being on antiretroviral treatment (ART)., Objectives: Aim of our study is to describe the clinical management of PLWHIV with LLV followed in a large cohort., Study Design: Retrospective cohort study., Results: We included 1607 adult patients over a three-year period (2015-2017). Follow up continued until June, 30th 2019 or last available visit. We observed a low incidence of LLV (0.9 % in 2015, 0.7 % in 2016 and 0.4 % in 2017), with a total of 21 patients with persistent LLV (pLLV), i.e. two consecutive HIV-RNA determinations of 50-500 copies/ml after at least 4 months of viral suppression. Among them, 12 had low compliance to treatment. Genotype resistance test (GRT) was performed in 14 patients and demonstrated at least one resistance mutation in 85.7 %. We described three categories of patients with pLLV: i) those whose ART regimen was not adequate based on GRT; ii) those with presumed suboptimal drug exposure, consequence of low adherence and/or drug-drug interactions and iii) those in which pLLV remained unexplained. For the first two categories, optimization or intensification of ART regimen led to viral suppression in >80 % of patients. We observed only 2 (9.5 %) virological failures and 1 (4.8 %) persistence of LLV in patients who did not switch ART., Conclusions: In our cohort, the rate of LLV showed a decline in most recent years. Adherence and previous GRT should be carefully considered with the aim of further reducing the phenomenon., (Copyright © 2019 Elsevier B.V. All rights reserved.)