Despite global vaccination efforts, immunocompromized patients remain at high risk for COVID‐19‐associated morbidity. In particular, patients with impaired humoral immunity have shown a high risk of persistent infection. We report a case series of adult patients with B cell malignancies and/or undergoing B cell targeting therapies with persisting SARS‐CoV‐2 infection and treated with a combination antiviral therapy of remdesivir and nirmatrelvir/ritonavir, in three Italian tertiary academic hospitals. A total of 14 patients with impaired adaptive humoral immunity and prolonged SARS‐CoV‐2 infection were treated with the dual antiviral therapy. The median age was 60 (IQR 56–68) years, and 11 were male. Twelve patients had B cell lymphoma, one patient had chronic lymphocytic leukemia and one patient had multiple sclerosis. Thirteen out of 14 patients had received prior B cell‐targeting therapies, consisting of anti‐CD20 monoclonal antibodies in 11 patients, and chimeric antigen receptor T therapy in 2 patients. The median time between diagnosis and therapy start was 42.0 (IQR 35–46) days. Seven patients had mild, 6 moderate and one severe disease. Nine patients had signs of interstitial pneumonitis on chest computed tomography scans before treatment. The median duration of nirmatrelvir/ritonavir and remdesivir combination therapy was 10 days. All patients showed resolution of COVID‐19‐related symptoms after a median of 6 (IQR 4–11) days and viral clearance after 9 (IQR 5–11) days. Combination therapy with remdesivir and nirmatrelvir/ritonavir is a promising treatment option for persistent COVID‐19 in immunocompromized patients with humoral immunity impairment, worthy of prospective comparative trials.

Correlation between COVID-19 and superinfections has been investigated, but remains to be fully assessed. In this multicenter study we report the impact of the pandemic on bloodstream infections. This study includes all patients with a BSI admitted to four Italian hospitals between January 1st and June 30th, 2020. Clinical, demographic, and microbiologic data were compared with those of patients hospitalized during the same period of 2019. Among 26,012 patients admitted in the first semester of 2020, 1,182 had COVID-19. In patients with COVID-19, we observed 107 BSIs, with an incidence rate of 8.19 episodes per 1000 patient-days. This incidence was significantly higher than in patients without COVID-19 (2.72/1000 patient-days) and in patients admitted in 2019 (2.76/1000 patient-days). In comparison with patients without COVID-19, BSIs onset in patients with COVID-19 was delayed during the course of hospitalization (16.0 vs 5 days). Thirty-day mortality among patients with COVID-19 was 40.2%, significantly higher than in patients without COVID-19 (23.7%). BSIs in patients with COVID-19 were frequently caused by MDR pathogens, which were often center-dependent. BSIs are a frequent secondary infection in patients with COVID-19, characterized by an increased risk during hospitalization and potentially burdened with high mortality.

Objectives: The objective of this study was to explore the relationship between pharmacokinetic/pharmacodynamic (PK/PD) target attainment of continuous-infusion (CI) meropenem and microbiological outcome in critical COVID-19 patients with documented Gram-negative superinfections. Methods: Patients receiving CI meropenem for documented Gram-negative infections at the COVID ICU of the IRCCS Azienda Ospedaliero-Universitaria di Bologna and undergoing therapeutic drug monitoring from January 2021 to February 2022 were retrospectively assessed. Average steady-state meropenem concentrations (C_ss) were calculated and the C_ss/MIC ratio was selected as a pharmacodynamic parameter of meropenem efficacy. The C_ss/MIC ratio was defined as optimal if ≥4, quasi-optimal if between 1 and 4, and suboptimal if <1. The relationship between C_ss/MIC and microbiological outcome was assessed. Results: Overall, 43 critical COVID-19 patients with documented Gram-negative infections were retrieved. Combination therapy was implemented in 26 cases. C_ss/MIC ratios were optimal in 27 (62.8%), quasi-optimal in 7 (16.3%), and suboptimal in 9 cases (20.9%). Microbiological failure occurred in 21 patients (48.8%), with no difference between monotherapy and combination therapy (43.8% vs. 53.8%; p = 0.53). The microbiological failure rate was significantly lower in patients with an optimal C_ss/MIC ratio compared to those with a quasi-optimal or suboptimal C_ss/MIC ratio (33.3% vs. 75.0%; p = 0.01). Conclusion: Suboptimal attainment of meropenem PK/PD targets may be a major determinant impacting on microbiological failure in critical COVID-19 patients with Gram-negative superinfections.

Background: Carbapenem‐resistant Enterobacterales (CRE) colonisation at liver transplantation (LT) increases the risk of CRE infection after LT, which impacts on recipients’ survival. Colonization status usually becomes evident only near LT. Thus, predictive models can be useful to guide antibiotic prophylaxis in endemic centres.Aims: This study aimed to identify risk factors for CRE colonisation at LT in order to build a predictive model.Methods: Retrospective multicentre study including consecutive adult patients who underwent LT, from 2010 to 2019, at two large teaching hospitals. We excluded patients who had CRE infections within 90 days before LT. CRE screening was performed in all patients on the day of LT. Exposure variables were considered within 90 days before LT and included cirrhosis complications, underlying disease, time on the waiting list, MELD and CLIF‐SOFA scores, antibiotic use, intensive care unit and hospital stay, and infections. A machine learning model was trained to detect the probability of a patient being colonized with CRE at LT.Results: A total of 1544 patients were analyzed, 116 (7.5%) patients were colonized by CRE at LT. The median time from CRE isolation to LT was 5 days. Use of antibiotics, hepato‐renal syndrome, worst CLIF sofa score, and use of beta‐lactam/beta‐lactamase inhibitor increased the probability of a patient having pre‐LT CRE. The proposed algorithm had a sensitivity of 66% and a specificity of 83% with a negative predictive value of 97%.Conclusions: We created a model able to predict CRE colonization at LT based on easy‐to‐obtain features that could guide antibiotic prophylaxis image

Conditions favouring persistent enterococcal bacteraemia (p-EB) have not been fully investigated yet. The aim of our study is to analyse risk factors for p-EB and its impact on mortality. International two-centre retrospective study of all hospitalised adults with enterococcal bacteraemia managed with follow-up blood cultures (BCs) during the period 2011-2019. Exclusion criteria were: (1) death within 72 hours from index BCs and (2) polymicrobial bacteraemia. Primary endpoint was p-EB, defined as further isolation of the same species of Enterococcus spp. from BCs after at least 72 hours of appropriate antibiotic therapy. Multivariable logistic regression model was performed to assess risk factors for p-EB. The impact of p-EB on 30-day mortality was assessed by Kaplan-Meier survival curve and Cox regression multivariable model. During the study period, 244 enterococcal bacteraemia were diagnosed. P-EB were 13.5% (33/244). At multivariable analysis, factors independently associated with p-EB were hematologic malignancy (OR 4.60 [95% CI 1.32-16.00], P = 0.01), infective endocarditis (OR 7.99 [95% CI 2.20-28.9], P = 0.002), and use of daptomycin as initial treatment (OR 4.50 [95% CI 1.29-15.61], P = 0.018). Mortality rate was higher in the p-EB group (32% vs. 18%). Kaplan-Meier survival curve showed that patients with p-EB were less likely to survive at 30 days from index BCs (log-rank P = 0.002). Using a Cox regression model, independent predictors of 30-day mortality were hematologic malignancy (HR 2.30 [95% CI 1.02-4.11], P = 0.043), p-EB (HR 1.93 [95% CI 0.92-4.04], P = 0.08), and septic shock (HR 5.92 [95% CI 2.17-16.30], P = 0.001). P-EB was diagnosed mainly in very fragile patients and in those receiving daptomycin as frontline therapy. P-EB may have an impact on mortality.

(1) Background: To explore the impact of the degree of inflammation on voriconazole exposure in critically ill patients affected by COVID-associated pulmonary aspergillosis (CAPA); (2) Methods: Critically ill patients receiving TDM-guided voriconazole for the management of proven or probable CAPA between January 2021 and December 2022 were included. The concentration/dose ratio (C/D) was used as a surrogate marker of voriconazole total clearance. A receiving operating characteristic (ROC) curve analysis was performed by using C-reactive protein (CRP) or procalcitonin (PCT) values as the test variable and voriconazole C/D ratio > 0.375 (equivalent to a trough concentration [C_min] value of 3 mg/L normalized to the maintenance dose of 8 mg/kg/day) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated; (3) Results: Overall, 50 patients were included. The median average voriconazole C_min was 2.47 (1.75–3.33) mg/L. The median (IQR) voriconazole concentration/dose ratio (C/D) was 0.29 (0.14–0.46). A CRP value > 11.46 mg/dL was associated with the achievement of voriconazole C_min > 3 mg/L, with an AUC of 0.667 (95% CI 0.593–0.735; p < 0.001). A PCT value > 0.3 ng/mL was associated with the attainment of voriconazole C_min > 3 mg/L (AUC 0.651; 95% CI 0.572–0.725; p = 0.0015). (4) Conclusions: Our findings suggest that in critically ill patients with CAPA, CRP and PCT values above the identified thresholds may cause the downregulation of voriconazole metabolism and favor voriconazole overexposure, leading to potentially toxic concentrations.