31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Case series of cefiderocol for salvage therapy in carbapenem-resistant Gram-negative infections

Purpose: This case series describes real-world utilization of cefiderocol and associated clinical outcomes in the setting of carbapenem-resistant Gram-negative bacterial infections. Methods: Adult hospitalized patients administered at least 5 days of cefiderocol as definitive treatment from October 1, 2020 to September 16, 2021 were included in this retrospective cohort analysis. The primary outcome was clinical success defined as a composite of 30 day survival, resolution of infection, and absence of 30 day recurrence of the same organism. Results: Among 24 patients, pneumonia (19, 79%) was the most common source of infection with Acinetobacter baumannii (14, 58%) and P. aeruginosa (10, 42%) as the predominant organisms isolated. Cefiderocol monotherapy was used as definitive treatment in 16 (67%) patients. Eleven patients (46%) met clinical success. Thirty-day mortality occurred in ten (42%) patients while seven (29%) patients had recurrence of infection. Thirteen out of 21 total isolates (62%) tested for susceptibility were deemed susceptible. Of the 16 patients with available susceptibility, 9 (56%) had an infection where all isolated organisms were susceptible to cefiderocol. Conclusions: Our results provide additional insight into the in vivo activity of cefiderocol. Cefiderocol remains a salvage option for carbapenem-resistant Gram-negative organisms

Antimicrobial prescribing after rapid influenza PCR implementation in the emergency department

Intro:Influenza shares common symptoms with bacterial pneumonia, which may result in unnecessary antibiotic prescriptions in the emergency department (ED) when the diagnosis is unknown. Rapid influenza polymerase chain reaction (PCR) tests have reduced turnaround times compared to standard multiplex PCR respiratory panels allowing for earlier diagnosis, which may improve antimicrobial stewardship outcomes in the ED. This study aims to compare antibiotic and antiviral use before and after deployment of the rapid influenza PCR in the ED. Methods:This single-center, retrospective, cohort study included pediatric and adult patients discharged from the ED with a positive influenza test using a standard multiplex PCR respiratory panel (January 2017 - July 2019) or rapid PCR (July 2019 - February 2020). The primary endpoint was number of antibiotic prescriptions pre- and post-implementation of the rapid influenza PCR in the ED. Secondary endpoints included number of antiviral prescriptions, duration of antimicrobial therapy, test turnaround time, ED length of stay, 30-day readmission, and adverse events. A multivariable logistic regression evaluated patient factors associated with antimicrobial prescribing. Results:A total of 620 positive influenza results were identified with 280 patients (standard multiplex PCR = 33; rapid PCR = 247) meeting inclusion criteria. Patients were less likely to be prescribed antibiotics (39.4% vs 8.9%, OR 0.15, 95% CI 0.067-0.34) and more likely to be prescribed antivirals (24.2% vs 61.1%, OR 4.92, 95% CI 2.13-11.34) with the rapid influenza PCR. Rapid influenza PCR significantly reduced ED length of stay (4.9 vs 3.4 h, p \u3c 0.01) and test turnaround time (27 h vs 3.5 h, p \u3c 0.01). Patients at high risk for complications associated with influenza were more likely to be prescribed antiviral therapy (22.7% vs 67.8%, OR 7.16, 95% CI 2.52-20.40). Based on the regression analysis conducted, asthma, (OR 3.5, 95% CI 1.48-8.26), immunosuppression (OR 9.6, 95% CI 1.18-78.2), and age Conclusion:Implementation of a rapid influenza PCR in the ED reduced antibiotic use and optimized antiviral therapy for patients with influenza including those at higher risk of complications

Fluoroquinolone versus Beta-Lactam Oral Step-Down Therapy for Uncomplicated Streptococcal Bloodstream Infections

Fluoroquinolones (FQs) are often preferred as oral step-down therapy for bloodstream infections (BSIs) due to favorable pharmacokinetic parameters; however, they are also associated with serious adverse events. The objective of this study was to compare clinical outcomes for patients who received an oral FQ versus an oral beta-lactam (BL) as step-down therapy for uncomplicated streptococcal BSIs. This multicenter, retrospective cohort study analyzed adult patients who completed therapy with an oral FQ or BL with at least one blood culture positive for a Streptococcus species from 1 January 2014 to 30 June 2019. The primary outcome was clinical success, defined as the lack of all-cause mortality, recurrent BSI with the same organism, and infection-related readmission at 90 days. A multivariable logistic regression model for predictors of clinical failure was conducted. A total of 220 patients were included, with 87 (40%) receiving an FQ and 133 (60%) receiving a BL. Step-down therapy with an oral BL was noninferior to an oral FQ (93.2% versus 92.0%; mean difference, 1.2%; 90% confidence interval [CI], -5.2 to 7.8). No differences were seen in 90-day mortality, 90-day recurrent BSI, 90-day infection-related readmission, or 90-day incidence of Clostridioides difficile-associated diarrhea. Predictors of clinical failure included oral step-down transition before day 3 (odds ratio [OR] = 5.18; 95% CI, 1.21, 22.16) and low-dose oral step-down therapy (OR = 2.74; 95% CI, 0.95, 7.90). Our results suggest that oral step-down therapy for uncomplicated streptococcal BSI with a BL is noninferior to an FQ

Impact of mandatory infectious diseases consultation and real-time antimicrobial stewardship pharmacist intervention on Staphylococcus aureus bacteremia bundle adherence

Background: The purpose of this study was to evaluate the impact of infectious diseases consultation (IDC) and a real-time antimicrobial stewardship (AMS) review on the management of Staphylococcus aureus bacteremia (SAB). Methods: This retrospective study included adult inpatients with SAB from January 2016 to December 2018 at 7 hospitals. Outcomes were compared between 3 time periods: before mandatory IDC and AMS review (period 1), after mandatory IDC and before AMS review (period 2), and after mandatory IDC and AMS review (period 3). The primary outcome was bundle adherence, defined as appropriate intravenous antimicrobial therapy, appropriate duration of therapy, appropriate surveillance cultures, echocardiography, and removal of indwelling intravenous catheters, if applicable. Secondary end points included individual bundle components, source control, length of stay (LOS), 30-day bacteremia-related readmission, and in-hospital all-cause mortality. Results: A total of 579 patients met inclusion criteria for analysis. Complete bundle adherence was 65% in period 1 (n = 241/371), 54% in period 2 (n = 47/87), and 76% in period 3 (n = 92/121). Relative to period 3, bundle adherence was significantly lower in period 1 (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.37-0.93; P = .02) and period 2 (OR, 0.37; 95% CI, 0.20-0.67; P = .0009). No difference in bundle adherence was noted between periods 1 and 2. Significant differences were seen in obtaining echocardiography (91% vs 83% vs 100%; P \u3c .001), source control (34% vs 45% vs 45%; P = .04), and hospital LOS (10.5 vs 8.9 vs 12.0 days; P = .01). No differences were noted for readmission or mortality. Conclusions: The addition of AMS pharmacist review to mandatory IDC was associated with significantly improved quality care bundle adherence

Clinical outcomes of patients treated for candida auris infections in a multisite health system, Illinois, USA

Candida auris is an emerging fungal pathogen that is typically resistant to fluconazole and is known to cause healthcare-associated outbreaks. We retrospectively reviewed 28 patients who had \u3e1 positive culture for C. auris within a multisite health system in Illinois, USA, during May 2018-April 2019. Twelve of these patients were treated as inpatients for C. auris infections; 10 (83%) met criteria for clinical success, defined as absence of all-cause mortality, C. auris recurrence, and infection-related readmission at 30 days from the first positive culture. The other 2 patients (17%) died within 30 days. Most patients (92%) were empirically treated with micafungin. Four (14%) of 28 total isolates were resistant to fluconazole, 1 (3.6%) was resistant to amphotericin B, and 1 (3.6%) was resistant to echinocandins. Our findings describe low rates of antifungal resistance and favorable clinical outcomes for most C. auris patients

Oral fluoroquinolones for definitive treatment of gram-negative bacteremia in cancer patients

PURPOSE: Bloodstream infections (BSI) are significant causes of morbidity and mortality in cancer patients. These patients often receive 10 to 14 days of intravenous (IV) antibiotics. The objective of this study was to compare the outcomes of cancer patients transitioned from IV to oral (PO) therapy compared to continuation of IV treatment. METHODS: This was a single-center, retrospective cohort study of hospitalized adult cancer patients with gram-negative bacteremia. Patients transitioned to a PO fluoroquinolone (FQ) within 5 days were allocated to the IV-to-PO group, while the remaining patients comprised the IV group. The primary outcome was the composite of treatment failure, defined as infection-related readmission, infection recurrence, or inpatient mortality. A multivariable logistic regression model was constructed to account for confounding variables. Secondary outcomes assessed included infection-related length of stay (LOS), hospital LOS, and adverse events, such as Clostridioides difficile infection and catheter-related complications. RESULTS: The IV-to-PO group included 78 patients, while the remaining 133 patients were allocated to the IV group. Differences at baseline included more hematologic malignancy, neutropenia, ICU admissions, and higher Pitt bacteremia scores in the IV group. The rate of treatment failure was significantly higher in the IV group (24% vs 9%; p \u3c 0.01), which persisted in the logistic regression (aOR 3.5, 95% CI 1.3-9.1). The IV-to-PO group had decreased infection-related and hospital length of stay, as well as fewer catheter-related complications. CONCLUSIONS: The use of PO FQ may be considered for the definitive treatment of uncomplicated Enterobacterales BSI in cancer patients

Search for strongly interacting massive particles generating trackless jets in proton–proton collisions at s=13 TeV\sqrt{s} = 13\,\text {TeV}

International audienceA search for dark matter in the form of strongly interacting massive particles (SIMPs) using the CMS detector at the LHC is presented. The SIMPs would be produced in pairs that manifest themselves as pairs of jets without tracks. The energy fraction of jets carried by charged particles is used as a key discriminator to suppress efficiently the large multijet background, and the remaining background is estimated directly from data. The search is performed using proton–proton collision data corresponding to an integrated luminosity of 16.1$\,\text {fb}^{-1}$, collected with the CMS detector in 2016. No significant excess of events is observed above the expected background. For the simplified dark matter model under consideration, SIMPs with masses up to 100$\,\text {GeV}$ are excluded and further sensitivity is explored towards higher masses