Role of ribavirin in the treatment of hepatitis C virus-associated mixed cryoglobulinemia with interferon-free regimens.

Mixed cryoglobulinemia (MC) is the most common extrahepatic manifestation of chronic hepatitis C (CHC), with the presence of symptoms in 10-15% of cases. There have been encouraging data regarding immunological and clinical responses in patients treated with the novel combinations of direct-acting antivirals (DAAs), but the role of ribavirin (RBV) in the treatment of MC has not yet been demonstrated. We prospectively enrolled 132 patients affected by MC and CHC, and virological, immunological and clinical responses were evaluated at 12 weeks after completion of treatment. All subjects were treated with interferon (IFN)-free regimens according to clinical guidelines, with or without RBV. All patients achieved a virological response. A complete immunological response (CR) was observed in 71 subjects (53.8%), a partial response in 44 (33.3%), and no response in 17 (12.8%). Ten patients showed a complete resolution of symptoms (7.6%), and 31 showed a significant improvement (23.5%). CR was significantly higher in patients taking RBV (71.1 vs. 44.8%, p < 0.001) and in treatment-naïve patients (62.5 vs. 43.3%, p < 0.001). In logistic regression analysis, duration of HCV infection of less than 20 years (OR 2.448; 95% IC 1.335-6.202; p = 0.019), treatment-naïve status (OR 2.885; 95% IC 1.404-9.660; p = 0.025) and the use of RBV (OR 6.961; 95% IC 3.912-26.885; p < 0.001) were predictors of CR. In MC patients, IFN-free regimens are effective and well tolerated, and RBV seems to significantly increase the immunological response and promote a decline in cryocrit.

Treatment with daclatasvir and sofosbuvir for 24 weeks without ribavirin in cirrhotic patients who failed first-generation protease inhibitors.

BACKGROUND: Treatment of patients with chronic hepatitis C who failed the triple therapy with first generation of protease inhibitors is not still defined. The combined use of sofosbuvir (SOF) and daclatasvir (DCV) seems to be promising due to higher genetic barrier, good tolerance and effectiveness. METHODS: We described the treatment with this drug combination in a real-life cohort of 20 cirrhotic patients with genotype 1 who failed the triple therapy. RESULTS: 18 of them (90%) with Child-Pugh A, 11 (55%) with genotype 1a, 17 (85%) with more than 1 and 8 (40%) with more than 2 previous failed treatment; all patients had at baseline NS3 resistance-associated variants related to triple therapy failure. RBV was not administered due to anemia in previous treatments. The sustained virological response was 100%. CONCLUSION: Treatment with SOF + DCV without RBV for 24 weeks is safe and effective in cirrhotic patients who failed triple therapy with the first generation of protease inhibitors.

Efficacy of bezlotoxumab in preventing the recurrence of Clostridioides difficile infection: an Italian multicenter cohort study.

OBJECTIVES: Bezlotoxumab (BEZ) is a promising tool for preventing the recurrence of Clostridioides difficile infection (rCDI). The aim of the study was to emulate, in a real-world setting, the MODIFY trials in a cohort of participants with multiple risk factors for rCDI treated with BEZ in addition to the standard of care (SoC) versus SoC alone. METHODS: A multicenter cohort study was conducted including 442 patients with Clostridioides difficile infection from 2018 to 2022, collected from 18 Italian centers. The main outcome was the 30-day occurrence of rCDI. The secondary outcomes were (i) all-cause mortality at 30 days (ii) and the composite outcome (30-day recurrence and/or all-cause death). RESULTS: rCDI at day 30 occurred in 54 (12%): 11 in the BEZ + SoC group and 43 treated with SoC alone (8% vs 14%, odds ratio [OR] = 0.58, 95% confidence interval [CI]: 0.31-1.09, P = 0.09). The difference between BEZ + SoC versus SoC was statistically significant after controlling for confounding factors (adjusted OR = 0.40, 95% CI: 018-0.88, P = 0.02) and even more using the composite outcome (adjusted OR = 0.35, 95% CI: 0.17-0.73, P = 0.005). CONCLUSION: Our study confirms the efficacy of BEZ + SoC for the prevention of rCDI and death in a real-world setting. BEZ should be routinely considered among participants at high risk of rCDI regardless of age, type of Clostridioides difficile infection therapy (vancomycin vs fidaxomicin), and number of risk factors.

REDS study: Retrospective effectiveness study of dalbavancin and other standard of care of the same IV antibiotic class in patients with ABSSSI.

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.

Cefiderocol use in Gram negative infections with limited therapeutic options: Is combination therapy the key?

OBJECTIVES: To date limited information about cefiderocol use is provided by real life studies. Our aim is to evaluate characteristics and outcome of patients with Gram-negative infections with limited therapeutic options treated with cefiderocol in combination or monotherapy. METHODS: We retrospectively collected data on demographical, clinical characteristics and clinical cure, in-hospital and 30-days mortality, microbiological failure and Clostridioides difficile infections of all patients ≥ 18 years old treated with cefiderocol for ≥ 48 h. RESULTS: There were 18 patients of which 14 (77.8%) treated with cefiderocol in combination and 4 (22.2%) with monotherapy. Median age was 54.5 (IQR 35.25-65.75) vs 70.5 (IQR 57.5-78.25) years old, respectively and ward of admission was the ICU in the 78.57% vs 100% of cases. In the 50% vs 100% of cases infections were VAP with concomitant bloodstream infections. Median SOFA score was 10 (IQR 4.5-12.5) vs 5 (IQR 4-6) and APACHE II score was 13.5 (IQR 7.5-18) vs 16 (IQR 8.5-23.5), respectively. Isolated pathogen was carbapenems-resistant Acinetobacter baumannii in 78.57% vs 100% of cases. Median duration of cefiderocol treatment was 9.5 (IQR 7-13.25) vs 9 days (IQR 5.5-12.5) and in 77.8% patients it was used in combination therapy, of which 57.1% were colistin-spairing regimens. Clinical cure was achieved in 64.29% for combination therapy vs 75% of monotherapy treated patients, 30-days mortality rate was 28.57% vs 25% and 30-day ICU admission rate was 14.29% vs 50%, respectively. No statistically significant differences were observed between combination therapy and monotherapy treated patients. CONCLUSIONS: To date, no differences have been demonstrated between cefiderocol monotherapy or combination. Further studies are required to understand whether cefiderocol combination therapy could provide an advantage in outcome in seriously-ill patients.

Nodular Cutaneous Lesions in Immune-Compromised Hosts as a Clue for the Diagnosis of Disseminated Nocardiosis: From Bedside to Microbiological Identification.

BACKGROUND: Nocardia is a group of ubiquitous bacteria known to cause opportunistic infections in immunocompromised hosts, including those affected by malignancies and solid-organ or hematopoietic stem cell transplants. Pulmonary involvement, occurring in two-thirds of cases, is the most frequent presentation. Diagnosis might be challenging both because of microbiological technical issues, but also because of the variability of organ involvement and mimicry. METHODS: We describe four cases of disseminated nocardiosis caused by N. farcinica observed between September 2021 and November 2021 in immune-compromised hosts presenting with nodular cutaneous lesions that had raised a high degree of clinical suspect and led to microbiological identification through MALDI-TOF MS. RESULTS: Cutaneous involvement is typically reported in immunocompetent hosts with primary cutaneous nocardiosis with multiple forms of manifestation; nonetheless, disseminated nocardiosis rarely involves the skin and subcutaneous tissues, and this occurs as a result of metastatic spread. Our cases were disseminated nocardiosis in which the metastatic cutaneous involvement, even if rare, provided a clue for the diagnosis. CONCLUSIONS: The pathomorphosis of disseminated nocardiosis may have changed in the current years with more rapid spread due to advanced immunosuppression. For this reason, after clinical suspicion, the prompt start of an active targeted therapy based on rapid microbiological identification might potentially open the way to hopeful results, even in the most immune-compromised patients.

Real-Life Experience of Molnupiravir in Hospitalized Patients Who Developed SARS-CoV2-Infection: Preliminary Results from CORACLE Registry.

Real-life experience of molnupiravir treatment is lacking, especially in people hospitalized for underlying diseases not related to COVID-19. We conducted a retrospective analysis regarding molnupiravir therapy in patients with SARS-CoV-2 infection admitted for underlying diseases not associated with COVID-19. Forty-four patients were included. The median age was 79 years (interquartile range [IQR]: 51-93 years), and most males were 57,4%. The median Charlson Comorbidity Index and 4C score were, respectively, 5 (IQR: 3-10) and 9.9 (IQR: 4-12). Moreover, 77.5% of the patients had at least two doses of the anti-SARS-CoV-2 vaccine, although 10.6% had not received any SARS-CoV-2 vaccine. Frequent comorbidities were cardiovascular diseases (68.1%), and diabetes (31.9%), and most admissions were for the acute chronic heart (20.4%) or liver (8.5%) failure. After molnupiravir started, 8 (18.1%) patients developed acute respiratory failure, and five (11.4%) patients died during hospitalisation. Moreover, molnupiravir treatment does not result in a statistically significant change in laboratory markers except for an increase in the monocyte count (p = 0.048, Z = 1.978). Molnupiravir treatment in our analysis was safe and well tolerated. In addition, no patients' characteristics were found significantly related to hospital mortality or an increase in oxygen support. The efficacy of the molecule remains controversial in large clinical studies, and further studies, including larger populations, are required to fill the gap in this issue.

Impact of an empiric antimicrobial therapy manual on antimicrobial usage and multidrug resistant organism trends in a large Italian teaching hospital.

Aim: To evaluate the changes in antimicrobial consumption and multidrug-resistant microorganism trends after introducing an empiric antimicrobial therapy manual to support antimicrobial stewardship. Methods: A 4-year prospective interventional study assessed the effect of introducing an empiric antimicrobial therapy manual in medical and surgical wards during two periods: pre-intervention period (January 2015-May 2017) and post-intervention period (June 2017-December 2019). Outcomes included microorganism trends of bloodstream infections (BSI) for Klebsiella pneumoniae carbapenemase-producing bacteria (KPC), extended spectrum beta-lactamase ESBL-E. coli, meticillin-resistant Staphylococcus aureus (MRSA) and Candida albicans. Also, Clostridioides difficile infection (CDI) episodes were included. Rates were normalised per 1000 patient-days (PD). Antimicrobial consumption was assessed as defined daily dose (DDD)/1000 PD in interrupted time series analysis. Results: In medical wards, we observed a significant decrease in the consumption of piperacillin-tazobactam and a decrease in the trends of tigecycline and vancomycin consumption. In surgical wards, there was a significant decrease in consumption of fluoroquinolones and piperacillin-tazobactam. This decrease was maintained in trend for all the antimicrobials but was significant for tigecycline only. In medical wards, there was a significant reduction of MRSA and C. albicans. In surgical wards, we observed a decrease in MRSA, ESBL-E. coli, C. albicans and CDI. KPC cases decreased by 22.5% in medical wards and 74.3% in surgical wards. Conclusion: The results suggest that a persuasive educational approach to antimicrobial stewardship, with the introduction of an empiric antimicrobial manual and continuous education, resulted in reductions in both antimicrobial use and healthcare-associated BSI caused by multidrug-resistant organisms. More studies with longer follow up are needed to investigate the effect of antimicrobial stewardship on clinical outcomes.

Liver involvement and mortality in COVID-19: A retrospective analysis from the CORACLE study group.

Introduction: liver abnormalities are common in COVID-19 patients and associated with higher morbidity and mortality. We aimed to investigate clinical significance and effect on the mortality of abnormal liver function tests (ALFTs) in COVID-19 patients. Methods: we retrospectively evaluated in a multicentre study all patients admitted with confirmed diagnosis of COVID-19. Results: 434 patients were included in this analysis. Among overall patients, 311 (71.6%) had normal baseline ALT levels. 123 patients showed overall abnormal liver function tests (ALFTs) at baseline [101 ALFTs <2x UNL and 22 ≥2 UNL]. Overall in-hospital mortality was 14% and mean duration of hospitalization was 10.5 days. Hypertension (50.5%), cardiovascular diseases (39.6%), diabetes (23%) were frequent comorbidities and 53.7% of patients had ARDS. At multivariate analysis, the presence of ARDS at baseline (OR=6.11; 95% CI: 3.03-12.32; p<0.000); cardiovascular diseases (OR=4; 95% CI: 2.05-7.81; p<0.000); dementia (OR=3.93; 95%CI:1.87-8.26; p<0.000) and no smoking (OR=4.6; 95% CI: 1.45-14.61; p=0.010) resulted significantly predictive of in-hospital mortality. The presence of ALFTs at baseline was not significantly associated with mortality (OR=3.44; 95% CI=0.81-14.58; p=0.094). Conclusion: ALFTs was frequently observed in COVID-19 patients, but the overall in-hospital mortality was mainly determined by the severity of illness, comorbidities and presence of ARDS.

COVID-19 pneumonia: do not leave the corticosteroids behind!

The host inflammatory response is critical in the progression of lung injuries in patients with SARS-CoV-2. Corticosteroids (CS) have been widely used as immunomodulating agents, but the right timing, dosage and type of molecule are unknown. In fact, the early use of CS could facilitate the viral replication but late administration may not prevent the alveolar damage. Nevertheless, a short administration of high doses of CS in the early stage of the inflammatory phase resulted in favorable outcomes. Noteworthy, some inhaled CS inhibited in vitro the viral replication of SARS-CoV-2. We aimed to define the place in therapy for CS in COVID-19 infection describing the features of patients who may benefit from their administration.

Pulmonary Echinococcosis or Lung Hydatidosis: A Narrative Review.

Background: Lung hydatidosis is a zoonosis related to infection by the Echinococcus tapeworm species. Lung involvement in this condition is second only to the liver echinococcosis. Diagnosis ordinarily results from an accidental finding in a direct chest radiograph evaluation because of the delayed growth of the cysts. Moreover, a consistent treatment regimen or approach may not be feasible because of the variability of pulmonary echinococcosis. In this review, we expect to sum up the main features of lung hydatidosis with a perspective on medical and surgical treatment. Methods: Cochrane Library and PubMed were the databases used to perform a narrative literature review. Search terms included "pulmonary echinococcosis" and "lung hydatidosis." The MeSH terms were "lung" [All Fields] AND {"echinococcosis" [MeSH Terms] OR ("hydatidosis" [All Fields] OR "pulmonary" [All Fields] AND "echinococcosis" [All Fields] OR "hydatidosis." A search period from September 1980 to May 2020 was chosen to compare studies from different decades, given the changes in pulmonary echinococcosis management. Results: A uniform treatment regimen or approach may not be feasible because of the variability of pulmonary echinococcosis. No clinical trials have analyzed and compared all the diverse treatment approaches. Cyst size, characteristics, position in the lung and clinical presentation, and the availability of medical/surgical expertise and equipment are the mainstays of echinococcosis management. When feasible, surgery is as yet the principal therapeutic choice to eliminate the cysts; anti-parasitic drugs may minimize complications during high-risk surgery or be used as definitive therapy in some instances with contraindications to surgery. Conclusions: Lung hydatidosis management must become less heterogeneous. We support treatment directed to the subject established on the clinical scenario, host factors, and surgical risk. Strict cooperation in this process between infectious disease specialists and surgeons may optimize best practices to help create shared practical guidelines to simplify clinicians' decision-making. Furthermore, we need a consensus for lung hydatidosis treatment and inserting this disease to global surgery agenda will have a positive impact on acquiring high-quality data that enables us to create an evidence-based guideline for this disease.

Retreatment with sofosbuvir/velpatasvir in cirrhotic patients with genotype-4 who failed a previous interferon-free regimen: a case series.

BACKGROUND: The novel available interferon (IFN)-free regimens significantly improved the sustained virological response (SVR) in patients with chronic hepatitis C (CHC), without important side effects and with shorter duration of treatment. In a subset of patients, however, the treatment failure (TF) was due to the presence of resistance-associated substitutions (RAS) that lead to virological breakthrough (BT) or relapse. We analysed in this case series the role of RAS on the TF in cirrhotic patients with genotype (GT)4, treated with a previous IFN-free regimen, and retreated with the combination of sofosbuvir (SOF)/velpatasvir (VEL) for 12 or 24 weeks, without ribavirin (RBV). METHODS: We included in this analysis all patients with GT4 who failed a previous IFN-free treatment, with the presence of RAS at BT or relapse. All patients were retreated with a fixed combination of SOF/VEL for 12/24 weeks, without RBV. We evaluated the SVR and the MELD score change after the treatment. RESULTS: Seven patients were described. All were cirrhotic, Child-Pugh A (n=5), B (n=2); baseline RAS were detected in 4/7 subjects; at post-treatment detection, NS5 RAS were: F28S (n=1), Q30K (n=2), S30G (n=1), NS3 were: S122R (n=1), S122G (n=2), D168V (n=3). All retreated patients gained SVR. MELD score improved in all subjects with a median change of 3 points. No significant side effects or adverse events were reported. CONCLUSIONS: The combination SOF/VEL could be considered for the retreatment of cirrhotic GT4 patients who failed a previous IFN-free treatment with the presence of RAS in NS3 or NS5 regions.

Vitamin D pathway gene polymorphisms affecting daclatasvir plasma concentration at 2 weeks and 1 month of therapy.

AIM: Vitamin D (VD) influences genetic expression through its receptor (VDR). VD pathway gene polymorphisms seem to influence antiviral drug pharmacokinetics and therapeutic outcome/toxicity. We investigated the association between daclatasvir (DCV) plasma concentrations and genetic variants (SNPs) associated with the VD pathway. PATIENTS & METHODS: Chronic hepatitis C patients treated with DCV from 2014 to 2016 were included. Genotypes were assessed through real-time PCR and plasma concentrations through liquid chromatography. RESULTS: A total of 52 patients were analyzed. DCV levels were influenced by CYP24A1 rs2248359T>C polymorphism at 2 weeks and VDR Cdx2 A>G at 1 month of treatment. Linear regression analysis showed baseline BMI, alanine aminotransferase and hematocrit as significant predictors of DCV concentrations at 2 weeks, BMI and hematocrit at baseline, VDR Cdx2 AG/GG and FokI TC/CC at 1 month. CONCLUSION: These results showed a possible role of VD pathway gene polymorphisms in influencing DCV plasma concentrations, but further studies are required.