Comparison between available early antiviral treatments in outpatients with SARS-CoV-2 infection: a real-life study.

PURPOSE: To investigate the clinical impact of three available antivirals for early COVID-19 treatment in a large real-life cohort. METHODS: Between January and October 2022 all outpatients tested positive for SARS-CoV-2 referring to IRCCS S. Orsola hospital treated with an early antiviral therapy were enrolled. A comparison between patients treated with nirmatrelvir/ritonavir (NTV/r), molnupiravir (MPV) and remdesivir (RDV) was conducted in term of indications and outcome. To account for differences between treatment groups a propensity score analysis was performed. After estimating the weights, we fitted a survey-weighted Cox regression model with inverse-probability weighting with hospital admission/death versus clinical recovery as the primary outcome. RESULTS: Overall 1342 patients were enrolled, 775 (57.8%), 360 (26.8%) and 207 (15.4%) in MPV, NTV/r and RDV group, respectively. Median age was 73 (59-82) years, male sex was 53.4%. Primary indication was immunosuppression (438, 32.6%), the median time from symptom onset to drug administration was 3 [2-4] days. Overall, clinical recovery was reached in 96.9% of patients, with hospital admission rate of 2.6%. No significant differences were found in clinical recovery nor hospitalization. Cox regression showed a decreased probability of hospital admission/ death among prior vaccinated patients compared with unvaccinated (HR 0.31 [95%CI 0.14-0.70], p = 0.005]). No difference in hospitalization rates in early treatment compared to late treatment were found. CONCLUSIONS: No differences among MPV, NTV/r and RDV in terms of clinical recovery or hospitalization were found. Patients not vaccinated had a significant increased risk of hospitalization.

Tolerability of pulsed high-dose L-AmB as pre-emptive therapy in patients at high risk for intra-abdominal candidiasis: A phase 2 study (LAMBDA study).

BACKGROUND: Intra-abdominal candidiasis (IAC) has a high mortality rate. However, the correct management of a critically ill patient with suspected IAC remains unclear. The aim of this study was to evaluate the safety of pulsed high-dose liposomal amphotericin B (L-AmB) in patients with suspected IAC managed with a beta-D-glucan (BDG)-guided strategy. METHODS: This phase 2 prospective study enrolled adult patients with intra-abdominal sepsis following surgery. Patients received a single dose of L-AmB 5 mg/kg on day 1. On day 3, L-AmB was discontinued in patients with a negative basal BDG result, and continued (3 mg/kg/daily) in patients with a positive basal BDG result or microbiologically confirmed IAC. The primary endpoint was the occurrence of adverse events, defined using the Common Toxicity Criteria classification. RESULTS: In total, 40 patients were enrolled from January 2019 to August 2022. Fifteen (37.5%) patients were male, and the median age was 65 [interquartile range (IQR) 49-76] years. Thirty-one (77.5%) patients underwent urgent surgery, and the principal indication was secondary/tertiary peritonitis (n=22, 55%); half of the patients had undergone a previous surgical operation within the preceding 30 days. Five (12.5%) patients met the criteria for septic shock at enrolment. The median APACHE II score on admission to the intensive care unit was 12 (IQR 10-15). IAC was excluded in 33 (85%) patients, but IAC was probable and proven in five (12.5%) and two (5%) patients, respectively. The single dose of L-AmB 5 mg/kg was well tolerated in all patients, and no early or late severe adverse events related to the drug were reported. L-AmB was discontinued in 65% of patients following a negative basal BDG result. The all-cause 30-day mortality rate was 15%, and no deaths were related to L-AmB administration or uncontrolled IAC. The mortality rates for patients with and without proven IAC were 0% and 15.8%, respectively (P=0.99). CONCLUSIONS: The rate of proven IAC among critically ill high-risk patients was low (5%). A single dose of L-AmB 5 mg/kg, with prompt withdrawal in the case of a basal negative BDG result, seems to be a safe and effective approach in this population.

Impact on clinical outcome of follow-up blood cultures and risk factors for persistent bacteraemia in patients with gram-negative bloodstream infections: a systematic review with meta-analysis.

BACKGROUND: The clinical usefulness of follow-up blood cultures (FUBCs) in gram-negative bloodstream infections (GN-BSIs) represents a debated issue. OBJECTIVE: To assess the impact on the clinical outcome of FUBCs in patients with GN-BSI and to predict risk factors for persistent bacteraemia. DATA SOURCES: PubMed-MEDLINE, Scopus, and the Cochrane Library Database were independently searched until 24 June, 2022. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials, prospective, or retrospective observational studies, including patients affected by GN-BSIs. Primary endpoints were in-hospital mortality rate, and persistent blood stream infections were defined as FUBC-positive for the same pathogen isolated from index blood cultures (BCs). PARTICIPANTS: Hospitalized patients with documented GN-BSIs. INTERVENTION: Performance of FUBCs (defined as subsequent BCs collected at least 24 hours after index BCs). ASSESSMENT OF RISK OF BIAS: Quality of included studies was independently assessed according to the Cochrane Risk of Bias Tool and the Risk Of Bias In Non-randomized Studies of Interventions. METHODS OF DATA SYNTHESIS: Meta-analysis was performed by pooling odds ratio (OR) retrieved from studies providing adjustment for confounders using random-effect model with the inverse variance method. Risk factors for persistent blood stream infections were also assessed. RESULTS: A total of 3747 articles were screened, and 11 observational studies (6 assessing impact on outcome (N = 4631), and 5 investigating risk factors for persistent GN-BSI (N = 2566)), conducted between 2002 and 2020 were included. The execution of FUBCs was associated with a significantly lower risk of mortality (OR, 0.58; 95% CI, 0.49-0.70; I2 = 0.0%). The presence of end-stage renal disease (OR, 2.99; 95% CI, 1.77-5.05), central venous catheter (OR, 3.30; 95% CI, 1.82-5.95), infections due to extended-spectrum ß-lactamase-producing strains (OR, 2.25; 95% CI, 1.18-4.28), resistance to empirical treatment (OR, 2.70; 95% CI, 1.65-4.41), and unfavourable response at 48 hours (OR, 2.99; 95% CI, 1.44-6.24) emerged as independent risk factors for persistent bacteraemia. CONCLUSIONS: The execution of FUBCs is associated with a significantly low risk of mortality in patients with GN-BSIs. Our analysis could be useful to stratify patients at a high risk of persistent bacteraemia to optimize the use of FUBCs.

Effect of a Fourth Dose of mRNA Vaccine and of Immunosuppression in Preventing SARS-CoV-2 Breakthrough Infections in Heart Transplant Patients.

Patients with heart transplantation (HT) have an increased risk of COVID-19 disease and the efficacy of vaccines on antibody induction is lower, even after three or four doses. The aim of our study was to assess the efficacy of four doses on infections and their interplay with immunosuppression. We included in this retrospective study all adult HT patients (12/21-11/22) without prior infection receiving a third or fourth dose of mRNA vaccine. The endpoints were infections and the combined incidence of ICU hospitalizations/death after the last dose (6-month survival rate). Among 268 patients, 62 had an infection, and 27.3% received four doses. Following multivariate analysis, three vs. four doses, mycophenolate (MMF) therapy, and HT < 5 years were associated with an increased risk of infection. MMF ≥ 2000 mg/day independently predicted infection, together with the other variables, and was associated with ICU hospitalization/death. Patients on MMF had lower levels of anti-RBD antibodies, and a positive antibody response after the third dose was associated with a lower probability of infection. In HT patients, a fourth dose of vaccine against SARS-CoV-2 reduces the risk of infection at six months. Mycophenolate, particularly at high doses, reduces the clinical effectiveness of the fourth dose and the antibody response to the vaccine.

Relationship Between Immune Response to Severe Acute Respiratory Syndrome Coronavirus 2 Vaccines and Development of Breakthrough Infection in Solid Organ Transplant Recipients: The CONTRAST Cohort.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in solid organ transplant (SOT) recipients is associated with poorer antibody response (AbR) compared with non-SOT recipients. However, its impact on the risk of breakthrough infection (BI) has yet to be assessed. METHODS: Single-center prospective longitudinal cohort study enrolling adult SOT recipients who received SARS-CoV-2 vaccination during a 1-year period (February 2021 - January 2022), end of follow-up April 2022. Patients were tested for AbR at multiple time points. The primary end-point was BI (laboratory-confirmed SARS-CoV-2 infection ≥14 days after the second dose). Immunization (positive AbR) was considered an intermediate state between vaccination and BI. Probabilities of being in vaccination, immunization, and BI states were obtained for each type of graft and vaccination sequence using multistate survival analysis. Then, multivariable logistic regression was performed to analyze the risk of BI related to AbR levels. RESULTS: 614 SOT (275 kidney, 163 liver, 137 heart, 39 lung) recipients were included. Most patients (84.7%) received 3 vaccine doses. The first 2 consisted of BNT162b2 and mRNA-1273 in 73.5% and 26.5% of cases, respectively. For the third dose, mRNA-1273 was administered in 59.8% of patients. Overall, 75.4% of patients reached immunization and 18.4% developed BI. Heart transplant recipients showed the lowest probability of immunization (0.418) and the highest of BI (0.323); all mRNA-1273 vaccine sequences showed the highest probability of immunization (0.732) and the lowest of BI (0.098). Risk of BI was higher for non-high-level AbR, younger age, and shorter time from transplant. CONCLUSIONS: SOT patients with non-high-level AbR and shorter time from transplantation and heart recipients are at highest risk of BI.

Association of Patients' Epidemiological Characteristics and Comorbidities with Severity and Related Mortality Risk of SARS-CoV-2 Infection: Results of an Umbrella Systematic Review and Meta-Analysis.

The objective of this study was to assess the association between patients' epidemiological characteristics and comorbidities with SARS-CoV-2 infection severity and related mortality risk. An umbrella systematic review, including a meta-analysis examining the association between patients' underlying conditions and severity (defined as need for hospitalization) and mortality of COVID-19, was performed. Studies were included if they reported pooled risk estimates of at least three underlying determinants for hospitalization, critical disease (ICU admission, mechanical ventilation), and hospital mortality in patients diagnosed with SARS-CoV-2 infection. Evidence was summarized as pooled odds ratios (pOR) for disease outcomes with 95% confidence intervals (95% CI). Sixteen systematic reviews investigating the possible associations of comorbidities with severity or death from COVID-19 disease were included. Hospitalization was associated with age > 60 years (pOR 3.50; 95% CI 2.97−4.36), smoking habit (pOR 3.50; 95% CI 2.97−4.36), and chronic pulmonary disease (pOR 2.94; 95% CI 2.14−4.04). Chronic pulmonary disease (pOR 2.82; 95% CI 1.92−4.14), cerebrovascular disease (pOR 2.74; 95% CI 1.59−4.74), and cardiovascular disease (pOR 2.44; 95% CI 1.97−3.01) were likely to be associated with increased risk of critical COVID-19. The highest risk of mortality was associated with cardiovascular disease (pOR 3.59; 95% CI 2.83−4.56), cerebrovascular disease (pOR 3.11; 95% CI 2.35−4.11), and chronic renal disease (pOR 3.02; 95% CI 2.61−3.49). In conclusion, this umbrella systematic review provides a comprehensive summary of meta-analyses examining the impact of patients' characteristics on COVID-19 outcomes. Elderly patients and those cardiovascular, cerebrovascular, and chronic renal disease should be prioritized for pre-exposure and post-exposure prophylaxis and early treatment.

Neutralizing monoclonal antibodies for early treatment of hospital-acquired SARS-CoV-2 infection in hematologic patients.

Efficacy of early treatment with anti-SARS-CoV-2 spike protein monoclonal antibodies (mAbs) for nosocomial SARS-CoV-2 infection in hematologic patients is unknown. Retrospective, cohort study conducted in four Italian teaching hospitals. We included adult patients with hematologic malignancies and hospital-acquired SARS-CoV-2 infection diagnosed between November 2020 and December 2021. The principal exposure variable was administration of mAbs. The primary endpoint was clinical failure dea composite outcome of mortality and/or invasive and noninvasive ventilation within 90 days from infection onset. We included 52 patients with hospital-acquired SARS-CoV-2 infection. Males were 29 (60%), median age was 62 (interquartile range [IQR] 48-70). Forty-five (86%) patients were on chemotherapy or had received chemotherapy within 30 days. MAbs were administered in 19/52 (36%) patients. Clinical failure occurred in 22 (42%) patients; 21% (4/19) in mAbs group versus 54% (18/33) in non-mAbs group (p = 0.03). Other predictors of clinical failure were older age (median [IQR] 69 [61-72] versus 58 [46-66], p = 0.001), and higher Charlson comorbidity index (median [IQR], 5 [3.25-5] versus 3 [2-5], p = 0.002). At multivariable Cox regression model, mAbs were independently associated with a significantly lower rate of clinical failure (HR 0.11, 95% CI 0.01-0.85, p = 0.01), after adjusting for confounders. In conclusion, mAbs are promising for early treatment of hematologic patients with healthcare-related SARS-CoV-2 infection.

A retrospective multicentre study on dalbavancin effectiveness and cost-evaluation in sternotomic wound infection treatment: DALBA SWIT Study.

OBJECTIVE: To evaluate the cost-effectiveness of dalbavancin compared with standard of care (SoC) treatment as daptomycin or teicoplanin in patients with sternal wound infections (SWI). METHODS: Multicentre retrospective study of patients diagnosed with SWI from January 2016 to December 2019 at two cardiac surgery facilities treated with dalbavancin, teicoplanin or daptomycin. Patients with SWI treated with dalbavancin were compared with SoC to evaluate resolution of infection at 90 and 180 days from infection diagnosis, length of stay (LoS) and management costs. RESULTS: 48 patients with SWI were enrolled, 25 (50%) male, median age 67 (60-73) years, Charlson index score 5 (4-7). Fifteen patients were treated with dalbavancin (31%) and 33 with SoC (69%): teicoplanin in 21 (63%), and daptomycin in 12 (37%). Staphylococcus species were the most frequent isolates (44, 92%), mostly (84%) resistant to methicillin. All patients were treated with surgical debridement followed by negative pressure wound therapy. Wound healing at day 90 and 180 was achieved in 46 (95.8%) and 34 (82.9%) of patients, respectively. A shorter length of hospitalization in patients treated with dalbavancin compared with SoC [12 (7-18) days vs 22 (12-36) days, p:0.009] was found. Treatment with dalbavancin resulted in total cost savings of €16 026 (95% CI 5976-26 076, P < 0.001). Savings were mainly related to the LoS that was significantly shorter in the dalbavancin group, generating significantly lower cost compared to SoC group. CONCLUSION: Dalbavancin treatment of sternal wound infections is effective and seems to reduce hospitalization length, leading to significantly lower costs.

Out-of-Hospital Treatment of Hepatitis C Increases Retention in Care among People Who Inject Drugs and Homeless Persons: An Observational Study.

BACKGROUND: People who inject drugs (PWID) and homeless people represent now a large reservoir of Hepatitis C virus (HCV) infection. However, Hepatis C elimination programs can barely reach these subgroups of patients. We aimed to evaluate and compare the retention in care among these difficult-to-treat patients when managed for HCV in hospital or in an out-of-hospital setting. METHODS: In our retrospective study, we categorized the included patients (PWID and homeless persons) into two groups according to whether anti-HCV treatment was offered and provided in a hospital or an out-of-hospital setting. We run logistic regressions to evaluate factors associated with retention in care (defined as the completion of direct antiviral agents (DAAs) therapy). RESULTS: We included 56 patients in our study: 27 were in the out-of-hospital group. Overall, 33 patients completed DAAs therapy. A higher rate of retention in care was observed in the out-of-hospital group rather than in-hospital group (p = 0.001). At the univariate analysis, retention in care was associated with the out-of-hospital management (p = 0.002) and with a shorter time between the first visit and the scheduled start of DAAs (p = 0.003). CONCLUSIONS: The choice of treatment models that can better adapt to difficult-to-treat populations, such as an out-of-hospital approach, will be important for achieving the eradication of HCV infection.

Improvement in liver steatosis after the switch from a ritonavir-boosted protease inhibitor to raltegravir in HIV-infected patients with non-alcoholic fatty liver disease.

Background: The ritonavir-boosted protease inhibitor (PI/r) use has been associated with several metabolic abnormalities, and the non-alcoholic fatty liver disease (NAFLD) is becoming a very frequent comorbidity among HIV-infected patients. Methods: We performed an observational, prospective study of HIV-infected patients with NAFLD, receiving one PI/r plus two nucleoside analogues, who switched from the PI/r to raltegravir or were treated only with lifestyle modification, maintaining antiretroviral therapy unchanged. Changes in liver steatosis after 12 months were evaluated by transient elastography and measurement of controlled attenuation parameter (CAP). Results: As a whole, 61 patients (46 males; median age, 55.4 years) were enrolled, and 32 of them have been switched from PI/r to raltegravir. At baseline, median CAP was 259 dB/m, 28 (45.9%) subjects had a moderate-to-severe hepatic steatosis (CAP ≥260 dB/m), and 19 patients (31.1%) had elevated aminotransferases. Type-2 diabetes mellitus was present in 5 persons, and chronic HCV coinfection in 4. At month 12, the median decrease in CAP values was -27 dB/m in patients switched to raltegravir and -11 dB/m in those with unchanged cART (p = .021). The number of patients with CAP ≥260 dB/m decreased from 16 to 6 (-62.5%) in patients switched to raltegravir and from 12 to 8 (-33.3%) in the other group (p = .037). Conclusion: After 12 months, HIV-infected patients with NAFLD switching from a PI/r to raltegravir showed a significantly greater decrease in the hepatic steatosis degreee in comparison with those with unchanged cART and treated only with lifestyle modification.

Improvement in insulin sensitivity and serum leptin concentration after the switch from a ritonavir-boosted PI to raltegravir or dolutegravir in non-diabetic HIV-infected patients.

OBJECTIVES: An observational, prospective, cohort study was performed to assess changes in insulin sensitivity and serum leptin level after a switch from a ritonavir-boosted PI (PI/r) to raltegravir or dolutegravir in HIV-infected adults on stable combination ART (cART). METHODS: Non-diabetic HIV-infected patients receiving suppressive cART including tenofovir disoproxil fumarate/emtricitabine plus one PI/r, who underwent a switch from the PI/r to raltegravir (group A) or dolutegravir (group B), were enrolled in the study. Serum levels of insulin, leptin and the homeostasis model assessment of insulin resistance (HOMA) index were evaluated during a 12 month follow-up. RESULTS: Overall, 86 patients were enrolled: 45 patients were included in group A and 41 were included in group B. The mean age was 45.7 years and 74 (86%) patients were male. After 12 months of follow-up, a significant reduction in the mean concentration of leptin and insulin was reported both in group A [-0.61 ng/mL (P < 0.001) and -2.5 mIU/L (P = 0.008), respectively] and in group B [-0.54 ng/mL (P = 0.005) and -2.1 mIU/L (P = 0.017), respectively], without a significant difference between the groups. A significant and comparable reduction in the mean HOMA index was reported both in group A [-0.55 (P = 0.004)] and in group B [-0.49 (P < 0.001)], as well as a significant decrease in lipid levels. CONCLUSIONS: In HIV-positive subjects on suppressive cART, the switch from a PI/r to raltegravir or dolutegravir led to a significant and comparable reduction in both HOMA index and serum leptin level, reflecting a similar and significant improvement in insulin sensitivity.