Antimicrobial Stewardship Interventions in Pediatric Oncology: A Systematic Review

Antimicrobial stewardship programs represent efficacious measures for reducing antibiotic overuse and improving outcomes in different settings. Specific data on pediatric oncology are lacking. We conducted a systematic review on the PubMed and Trip databases according to the PRISMA guidelines, searching for reports regarding antimicrobial stewardship in pediatric oncology and hematology patients. The aim of the study was to summarize the present literature regarding the implementation of antimicrobial stewardship programs or initiatives in this particular population, and provide insights for future investigations. Nine papers were included in the qualitative analysis: three regarding antifungal interventions, five regarding antibacterial interventions, and one regarding both antifungal and antibacterial stewardship interventions. Variable strategies were reported among the included studies. Different parameters were used to evaluate the impact of these interventions, including days of therapy per 1000-patient-days, infections with resistant strains, safety analysis, and costs. We generally observed a reduction in the prescription of broad-spectrum antibiotics and an improved appropriateness, with reduced antibiotic-related side effects and no difference in infection-related mortality. Antibiotic stewardship programs or interventions are effective in reducing antibiotic consumption and improving outcomes in pediatric oncology hematology settings, although stewardship strategies differ substantially in different institutions. A standardized approach needs to be implemented in future studies in order to better elucidate the impact of stewardship programs in this category of patients

THU-117-Evaluation of risk factors associated with failure to a first-line NS5A-containing regimen in HCV-infected patients naive to direct acting antivirals: Particular focus on natural resistance

Background and aims: This study aimed to evaluate the presence of natural resistance-associated- substitutions (RASs) and other pre-treatment risk-factors for failure in a large group of HCV-infected patients (pts) naive to direct-acting-antivirals (DAA) with an available outcome after their first-line NS5A inhibitor-containing regimen in Italy. Method: RASs in NS3/NS5A/NS5B (N = 1685/1497/1175) were analysed in 1947 DAA-naïve pts. Of them, 705 had an available outcome after a first-line NS5A-containing regimen recommended by the 2016/18 guidelines, with a baseline (BL) NS5A-test. HCV Sanger-sequencing was performed by home-made protocols. Potential differences between the sustained-virological-response (SVR) and virological-failure (VF) group were evaluated by Fisher’s exact test. A multivariable logistic-regression analysis was performed to define risk-factors associated to treatment-response. Results: Overall, 579/1947 (29.7%) pts showed at least one natural RASs, particularly NS5A-RAS was observed in 18.9% of pts. 705 pts (GT1a/b/g[200/214/1]-GT2a/c[84]-3a[141]-4a/d[65]) had an available outcome (656 with a SVR and 49 with a VF) after the following recommended NS5A- containing regimen: daclatasvir (DCV)/ledipasvir (LDV)/velpatasvir (VEL)+sofosbuvir (SOF)±ribavirin (RBV) (N = 125/130/161), 3D/2D (paritaprevir/ritonavir+ombitasvir ± dasabuvir)±RBV (N = 125/44), grazoprevir (GZR)+elbasvir (EBR)±RBV (N = 70), glecaprevir+pibrentasvir (G/P) (N = 50). By analysing retrospectively the BL samples, a higher prevalence of natural NS5A-RASs was observed before treatment in DAA-failures (18/49, 36.7%) vs SVR-pts (94/656, 14.3%; P < 0.001). Notably, ≥ 2 risk factors for failure were more frequently observed at BL among pts who experienced a VF to a DAA treatment (37/49, 75.5%) compared to those achieving SVR (295/656, 45.0%, P < 0.001). By multivariable logistic-regression high HCV-RNA, natural RAS, cirrhosis, previous IFN-failure were negatively associated with SVR (see figure). Interestingly, all 32 GT1-3 pts treated with G/P achieved SVR, with the exception of 1 GT3, who had a breakthrough and had at BL the NS5A RAS A30K and HCV-RNA > 800.000 IU/ml. All others were without (or only 1) risk-factor: notably none of them showed BL RASs regimen-related. Conclusion: The presence of specific pre-treatment risk-factor, such as RAS regimen-related, BL HCV-RNA > 800.000 IU/ml, cirrhosis and previous IFN-failure were associated with virological failure for some specific regimens and GTs

CSPG4: a prototype oncoantigen for translational immunotherapy studies

Abstract Thanks to striking progress in both the understanding of anti-tumor immune response and the characterization of several tumor associated antigens (TAA), a more rational design and more sophisticated strategies for anti-tumor vaccination have been possible. However, the effectiveness of cancer vaccines in clinical trial is still partial, indicating that additional studies are needed to optimize their design and their pre-clinical testing. Indeed, anti-tumor vaccination success relies on the choice of the best TAA to be targeted and on the translational power of the pre-clinical model used to assess its efficacy. The chondroitin sulfate proteoglycan-4 (CSPG4) is a cell surface proteoglycan overexpressed in a huge range of human and canine neoplastic lesions by tumor cells, tumor microenvironment and cancer initiating cells. CSPG4 plays a central role in the oncogenic pathways required for malignant progression and metastatization. Thanks to these features and to its poor expression in adult healthy tissues, CSPG4 represents an ideal oncoantigen and thus an attractive target for anti-tumor immunotherapy. In this review we explore the potential of CSPG4 immune-targeting. Moreover, since it has been clearly demonstrated that spontaneous canine tumors mimic the progression of human malignancies better than any other pre-clinical model available so far, we reported also our results indicating that CSPG4 DNA vaccination is safe and effective in significantly increasing the survival of canine melanoma patients. Therefore, anti-CSPG4 vaccination strategy could have a substantial impact for the treatment of the wider population of spontaneous CSPG4-positive tumor affected dogs with a priceless translational value and a revolutionary implication for human oncological patients

Extended Infusion of beta-Lactams for Bloodstream Infection in Patients With Liver Cirrhosis: An Observational Multicenter Study

Background. We analyzed the impact of continuous/extended infusion (C/EI) vs intermittent infusion of piperacillin-tazobactam (TZP) and carbapenems on 30-day mortality of patients with liver cirrhosis and bloodstream infection (BSI). Methods. The BICRHOME study was a prospective, multicenter study that enrolled 312 cirrhotic patients with BSI. In this secondary analysis, we selected patients receiving TZP or carbapenems as adequate empirical treatment. The 30-day mortality of patients receiving C/EI or intermittent infusion of TZP or carbapenems was assessed with Kaplan-Meier curves, Cox-regression model, and estimation of the average treatment effect (ATE) using propensity score matching. Results. Overall, 119 patients received TZP or carbapenems as empirical treatment. Patients who received C/EI had a significantly lower mortality rate (16% vs 36%, P = .047). In a Cox-regression model, the administration of C/EI was associated with a significantly lower mortality (hazard ratio [HR], 0.41; 95% confidence interval [CI], 0.11-0.936; P = .04) when adjusted for severity of illness and an ATE of 25.6% reduction in 30-day mortality risk (95% CI, 18.9-32.3; P = 25 (HR, 0.26; 95% CI, 0.08-0.92). At competing risk analysis, C/EI of beta-lactams was associated with significantly higher rates of hospital discharge (subdistribution hazard [95% CI], 1.62 [1.06-2.47]). Conclusions. C/EI of beta-lactams in cirrhotic patients with BSI may improve outcomes and facilitate earlier discharge