bluuebunny/crossref_metadata_2025_split huggingface dataset:
1182. The Real-World Use of Isavuconazole as Primary or salvage Therapy of Invasive Fungal infections in High-Risk Patients with Hematologic Malignancy or Stem Cell Transplant
Authors: dagher Hiba , Hachem Ray Y , Chaftari Anne-Marie , Jiang Ying , Ali Shahnoor , Deeba Rita , Shah Shivan , Raad Issam I , Raad Issam I 
Published: January 2021

Abstract

Background
Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among immunocompromised patients with hematologic malignancies (HM) and stem cell transplants (SCT). Isavuconazole was approved by FDA as a primary therapy for Invasive Aspergillosis (IA) and Mucormycosis. The aim of this study is to look at the real-world use of Isavuconazole in patients with HM and evaluate their clinical outcomes and safety.

Methods
We conducted a retrospective study of 200 HM patients at MD Anderson Cancer Center who had definite, probable or possible mold infections between April 2016 and January 2020 and were treated with Isavuconazole for a period of at least 7 days. Clinical and radiological findings were assessed at baseline and at 6 and 12 weeks of follow up.

Results
HM patients with IFIs were classified as definite (11), probable (66) and possible (123). IA was the most commonly isolated pathogen followed by mucor and candida. The majority of patients (65%) received prophylaxis with anti-mold therapy, 73% consisted of azoles and 22% of echinocandins. Isavuconazole was used as a primary therapy in 57.5% of patients, and as salvage therapy in 42.5%. The switch to Isavuconazole was driven by failure of the primary therapy in 50% of the cases and by adverse effects in 28%. These included elevated liver function tests (LFTs), subtherapeutic voriconazole levels and prolonged QT. Isavuconazole was used as monotherapy in 30% of the cases and combination in 70% mostly with a polyene (54%) and/or an echinocandin (27%). A favorable response with Isavuconazole was observed in 57% at 6 weeks of therapy. Adverse events possibly related to Isavuconazole were reported in 6 patients (3%) leading to drug discontinuation. These included 5 elevated transaminases and 1 nausea. All-cause mortality was reported in 46% of patients and IFI-attributable mortality in 25%.

Conclusion
Selecting Isavuconazole therapy was mainly driven by failure of other antifungal agents or adverse events to other antifungals such as increased LFTs, subtherapeutic voriconazole levels or prolonged QT. Isavuconazole seems to have a promising clinical response and a good safety profile as an antifungal therapy in high risk cancer patients with HM.

Disclosures
Issam I. Raad, MD, Citius (Other Financial or Material Support, Ownership interest)Cook Medical (Grant/Research Support)Inventive Protocol (Other Financial or Material Support, Ownership interest)Novel Anti-Infective Technologies (Shareholder, Other Financial or Material Support, Ownership interest)
1185. Association Between Blood Product Transfusion and Development of Hospital Acquired Infections or Mortality in Patients Admitted to the Hospital Wards. A Retrospective Case-Control Study
Authors: Aravagiri Arunmozhi S , Napatkamon Ayutyanont , Sharma Sabhyata , Collins Timothy , Ubbaonu Chimezie , Mufti Hoveda 
Published: January 2021

Abstract

Background
Transfusion of blood products has been shown to be associated with increased mortality and risk of infections in critically ill patients and following cardiac surgery [1-2]. However, there is scarce data evaluating this association in patients admitted to hospital wards. Here we seek to see if transfusion of blood products carries the same risk of infection and mortality in more stable patients.

Methods
This was a retrospective case-control study of patients admitted to the internal medicine wards who received packed red blood cells (PRBC), fresh frozen plasma (FFP) or platelet transfusions, using data from the HCA Healthcare administrative database from 2016 to 2019. Patients admitted with an infection, on steroids or other immunosuppressant medications were excluded. ICD-10 codes at discharge were used to determine hospital acquired infections (HAI). The presence of HAI was the dependent variable. A multivariable logistic regression was used to determine the effects of the independent variables on development of HAI after adjusting for age and Carlson’s Comorbidity Index. Odds ratios and 95% confidence intervals were calculated. Primary outcome of study was presence of HAI, while secondary outcome was mortality in transfused vs. non-transfused patients.

Results
A total of 1952 subjects were included in the study analysis. Of these, 653 or 33.4% had a HAI during their admission. Adjusted multivariable model showed transfusion of PRBC (OR 1.14, 95%CI 0.85-1.52), platelets (OR 1.41, 95% CI 0.93-2.10) or FFP (OR 1.27 95%CI 0.90-1.75) was not associated with increased odds of having a HAI. The multivariable model however, did show an increase in odds of mortality in patients who were transfused with PRBC (OR 2.51, 95%CI 1.78-3.54), platelets (OR 3.17, 95%CI 2.01-5.0) or FFP (OR 2.78, 95% CI 1.89-4.08) compared to non-transfused.

Conclusion
Our data failed to show association between transfusion of blood products and HAI. However, it showed there was significant increase in mortality in patients that had received blood products during their admission.

Disclosures
All Authors: No reported disclosures
1187. CFTR Function Impacts Proinflammatory Cytokine Expression of Bronchial Epithelial Cells During Pseudomonas aeruginosa and Staphylococcus aureus Infections
Authors: Phuong Melissa S , Sad Subash 
Published: January 2021

Abstract

Background
Cystic fibrosis (CF) is a genetic disease in which opportunistic respiratory infections are common, particularly with P. aeruginosa and S. aureus. It has been suggested that dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR) could impact host immune response to these infections. The aim of this study was to determine if dysfunction in the CFTR gene could impact host cell death and the expression of proinflammatory cytokines.

Methods
We used two human bronchial epithelial (HBE) cell lines NuLi-1 and CuFi-1, which were recovered from individuals without and with CF, respectively. THP-1 cells were also differentiated into a macrophage phenotype with 50ng/mL PMA, and 10 µM CFTRinh-172 was used to impair CFTR function in these cells. Laboratory reference strains PAO1 and S. aureus 6538 were used to conduct in vitro infections. Host cell death at various MOIs was evaluated using a neutral red uptake assay, and cytokine expression was measured using ELISAs.

Results
No differences in THP-1 cell death or cytokine expression were observed for infections with S. aureus 6538 or PAO1 with and without CFTRinh-172. No differences in cell death for infections with the HBE cells and either bacteria were noted. S. aureus 6538 induced higher levels of IL-1β when infecting CuFi-1 cells in comparison to NuLi-1 cells across all MOIs (P &lt; 0.001) and induced higher levels of IL-6 at an MOI of 100 (P &lt; 0.01). S. aureus 6538 also induced higher levels of IL-8 when infecting CuFi-1 cells in comparison to NuLi-1 at MOIs of 1 and 10 (P &lt; 0.05 and P &lt; 0.01, respectively). Meanwhile, PAO1 induced less IL-6 expression when infecting CuFI-1 cells at an MOI of 1 and 10 (P &lt; 0.01 and P &lt; 0.01, respectively). CuFi-1 cells infected with PAO1 had less IL-8 expression in comparison to infected NuLi-1 cells for all MOIs (P &lt; 0.01), but no differences in IL-1β expression were observed when infecting either cell line with PAO1.

Conclusion
Bronchial epithelial cells with and without functional CFTR appear to respond differently to infections with either P. aeruginosa or S. aureus. Further elucidating how various immune response pathways are impacted by CFTR dysfunction may lead to alternative approaches to therapy to reduce morbidity observed among CF patients.

Disclosures
All Authors: No reported disclosures
1195. Influence of Histoplasma capsulatum Infection on Endothelin-1 mRNA Gene Expression in Bone Marrow Derived Macrophages
Authors: Ajayi Eloho , Deepe George S , Buesing William R 
Published: January 2021

Abstract

Background
Endothelin-1 (ET-1) is increasingly recognized as an immune modulator; it exerts a pro-inflammatory effect by increasing the release of cytokines like interferon gamma. ET-1 is secreted by a variety of cells such as macrophages, neurons and endothelial cells. Activation of the endothelin system has been implicated in the pathogenesis of sepsis caused by bacteria, viruses and even parasites. However, there are no published studies that have explored the role of ET-1 in Histoplasma capsulatum infection. Studying the role of ET-1 in histoplasmosis is important because understanding its role in the host defense mechanism may serve as the foundation for future discovery of novel therapeutic options.

Methods
Bone marrow cells were isolated from mice and set up for tissue culture. Bone marrow derived macrophages (BMDM) were harvested after 5-7 days of incubation, and infected with varying ratios (0.5,1 and 5) of yeasts to macrophages. RNA was extracted from the BMDM after 3, 6, 24 and 48 hours of infection. For comparison, RNA was also extracted from uninfected BMDM at the same time points. Real-time PCR (polymerase chain reaction) was performed on complementary DNA. ET-1 (Edn1) messenger RNA (mRNA) gene expression was quantified relative to the expression of the house keeping /endogenous control gene that encodes for beta-2 microglobulin (B2m).

Results
In BMDM infected with H. capsulatum there was upregulation of Edn1 after 3, 6 and 24 hours of infection. During this same time points, the expression of ET-1 mRNA in the uninfected BMDM remained constant. Expression of Edn1 was highest in the BMDM infected with 5x H. capsulatum after 3 and 6 hours of infection. After 24 hours, the expression of ET-1 mRNA decreased markedly in all concentrations of H. capsulatum. At 48 hours post-infection the Edn1 was downregulated in the 0.5,1 and 5-fold quantities of H. capsulatum across all time the time intervals.
Figure 1

Conclusion
Results from this study indicate that H. capsulatum infection induced an upregulation of the Edn-1 in BMDM. This may correlate with an increase in levels of ET-1 production by the BMDM in the face of H. capsulatum infection. These results provide a platform in which to examine the influence of ET-1 on the host response to this fungus.

Disclosures
All Authors: No reported disclosures
1217. Clinical and Microbiological Characteristics of Patients with Bacteremia and Normal Procalcitonin at Single Tertiary Care Medical Center
Authors: Boussi Leora , Popli Tarun , Feola Nicholas , Nog Rajat 
Published: January 2021

Abstract

Background
Procalcitonin (PCT) is a serum biomarker used to diagnose bacterial infections and guide antibiotic therapy. Many studies highlight its high sensitivity, specificity, and negative predictive value for bacteremia. PCT &gt; 2ng/mL has been reported to be strongly indicative of systemic bacterial infection, with values of .5-2ng/mL suggesting localized infection and &lt; .5ng/mL strongly suggesting absence of infection. However, emerging reports have raised concerns about PCT in bacteremia, demonstrating low sensitivity. Few studies have characterized patients with bacteremia and low PCT. We aimed to analyze the clinical and microbiological characteristics of patients with bacteremia and PCT &lt; 2ng/mL.

Methods
Adult patients admitted at Westchester Medical Center with bacteremia and associated PCT level within 24 hours (hrs) prior to 48 hrs post blood culture collection from 1/1/2014-9/30/2019 were included. Demographic, clinical, laboratory, and microbiological data were retrospectively collected and analyzed.

Results
There were 414 total cases of bacteremia with an associated PCT level within 24 hrs prior to 48 hrs post blood culture collection. 209 of 414 (50.5%) patients had PCT &lt; 2ng/mL. Of these, 86 were excluded (73 contaminants, defined as bacteremia not causing systemic inflammation and not treated, 10 fungal cultures, and 3 lacking data). Of the remaining 123 (37.5%) patients with PCT &lt; 2ng/mL, 66 (53.7%) had PCT&lt;. 5ng/mL. The leading infection source was endovascular/line-related at 31.7%, followed by intraabdominal/gastrointestinal and urinary. 30.9% of bloodstream organisms were gram negative. Among these 123 patients with PCT &lt; 2ng/mL, in-hospital mortality with bacteremia clinically contributing to death was 13%.
Characteristics of patients with bacteremia and procalcitonin &lt; 2ng/mL

Conclusion
Despite literature supporting the use of PCT algorithms in initiation and de-escalation of antibiotics in patients with suspected bacterial infections, a substantial percentage of bacteremic patients can have low PCT but significant infection-related mortality. Therefore, PCT should not be the only factor utilized by clinicians in the management of such patients, including initiating or deescalating antibiotics. Further studies are needed to characterize patient characteristics as contributing factors for bacteremia with low PCT.

Disclosures
All Authors: No reported disclosures
1222. Fosfomycin Susceptibility Testing using the new ETEST®FO
Authors: Halimi Diane , Pompilio Marion , Fontaine Sandrine , Martelin Roland , Franceschi Christine , Zambardi Gilles 
Published: January 2021

Abstract

Background
Fosfomycin (FO) is a bactericidal antibiotic with a broad spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria. Oral FO is mainly used in the treatment of urinary tract infections, particularly those caused by E. coli and E. faecalis. In order to determine MICs to FO, the ETEST® FM is already available but the reading can be difficult especially with E. coli. To resolve this issue, a new ETEST® with FO, called ETEST® FO, has been developed (not FDA cleared, yet). The purpose of this study is to compare this new strip to the agar dilution reference method (AD) on a panel of E. coli and E. faecalis.

Methods
A total of 39 isolates comprising 20 E. coli (ESBL or CPE) and 19 E. faecalis (VRE or VSE) were tested by ETEST® FO and Agar dilution. The isolates were sub-cultured on Columbia agar plates supplemented with 5% sheep blood before testing. After incubation, suspensions of the isolates were prepared in 0.85% saline. These suspensions were used to inoculate both AD and ETEST® plates. Results were read after 16-20 hours incubation at 35°C +2°C in ambient air. Following CLSI QC guideline, 4 QC organisms were tested. Results were analyzed using the FDA/CLSI breakpoints for FO (S &lt; 64µg/mL, I=128 µg/mL, R&gt; 256 µg/mL). Performance was evaluated using FDA performance criteria, essential agreement (EA, ≥ 90%), category agreement (CA, ≥ 90%), major error rate (ME, ≤3.0%) and very major error rate (VME, ≤2.0%).

Results
All the QC strains MICs were within the CLSI ranges. For the panel results, see the table below:
Performance for ETEST® FO on E. coli and E. faecalis

Conclusion
This first and preliminary study shows that ETEST® FO can potentially meet the FDA acceptance criteria and could be a valuable tool for determining FO MIC for E. coli harboring various resistance mechanisms and E. faecalis including VRE. Moreover, in comparison with the current ETEST FM strip, this new strip brings a real reading improvement and resolve the issue for E. coli. The clinical study phase will determine the product’s performance.

Disclosures
Marion Pompilio, BioMérieux (Employee) Gilles Zambardi, biomerieux (Employee)
1225. Next-Generation Sequencing in Clinical Practice: A Survey of Infectious Disease Providers
Authors: Vasishta Shilpa , Graber Christopher J , Vijayan Tara 
Published: January 2021

Abstract

Background
Next-generation sequencing (NGS) has emerged as a promising diagnostic tool in Infectious Diseases (ID). The platform offers high sensitivity, detecting difficult-to-isolate organisms. However, limitations remain in employing NGS broadly, including high cost, unstandardized methods, and unclear significance of many results. To date, there is no consensus on appropriate use of NGS. Here, we describe perceived utility of NGS among ID physicians at one academic medical center.

Methods
A survey exploring four clinical scenarios was disseminated electronically to ID attendings and fellows. Scenarios #1 (immunocompetent patient without localizing signs) and #2 (immunosuppressed patient with localizing signs) were followed by questions exploring likelihood of sending NGS. Scenarios #3 (immunocompetent patient with prosthetic joint infection) and #4 (immunosuppressed patient with cavitary lung lesion) were followed by questions exploring interpretation of NGS data.

Results
Twenty-six physicians responded. Respondents were more likely to send NGS for an immunosuppressed than an immunocompetent patient (8/26 vs. 2/26 respondents, p=0.024), with more respondents noting in the latter casethat NGS might “yield unhelpful/misleading results” (26 /26 vs. 17/23, p=0.0054) or might “not be cost-effective” (21/26 vs. 13/23, p=0.066). Those with over five years of experience tended to be more likely to send NGS (8/27 vs. 2/23 responses across two scenarios, p=0.065), noting more frequently that NGS might “yield a diagnosis not otherwise considered” (16/25 vs. 6/23 responses, p=0.0084) and“avoid painful/high-risk testing” (16/26 vs. 8/23 responses, p=0.062). In scenarios with available NGS data, nearlyhalf (21/49 responses across two scenarios) favored obtaining further diagnostics.

Conclusion
Our results suggest that patient immunosuppression is a salient factor in determining clinical utility of NGS and that physician experience may affect utilization. While NGS is perceived as a useful adjunct to existing data to guide initial management, results are still interpreted with caution and rarely supersede more established methods for definitive diagnosis. Further study is needed to guide evidence-based NGS use.

Disclosures
All Authors: No reported disclosures
1243. Semi-Quantitative Benefit-Risk Assessment for a New Quadrivalent Meningococcal Conjugate Vaccine (MenACYW-TT) in Individuals 2 Years of Age and Older
Authors: Neveu David , Kürzinger Marie-Laure , Chen Aiying , Dhingra Mandeep S 
Published: January 2021

Abstract

Background
MenACYW-TT is a new quadrivalent meningococcal conjugate vaccine approved by the US FDA for use in individuals 2 years and older. We present the structured benefit-risk assessment conducted by Sanofi Pasteur in support of the initial biological license application for MenACYW-TT.

Methods
The safety and immunogenicity of MenACYW-TT in subjects ≥ 2 years was evaluated in 5 pivotal randomized, active-controlled clinical trials. Collectively, 4,919 subjects received either a single primary dose (n=4517) or a booster dose (n=402) of MenACYW-TT. A semi-quantitative framework was used to establish favorable and unfavorable effects of MenACYW-TT relative to comparators: MenACWY-CRM in children 2-9 years and adolescents 10-17 years, MenACWY-D in adolescents 10-17 years and adults 18-55 years, and MPSV4 in older adults ≥ 56 years. Benefit outcome measures included vaccine seroresponse and seroprotection (titers ≥ 1:8) at D30 evaluated by serum bactericidal assay using human complement, for each serogroup. Risk outcome measures included rates of solicited injection site and systemic reactions (including grade 3 reactions) within 7 days after vaccination, and rates of serious adverse events within 6 months after vaccination. The differences in rates for MenACWY-TT vs comparator vaccines were calculated along with 95% confidence intervals.

Results
For all benefit criteria, and in all age groups, rate differences favored MenACYW-TT in meningococcal vaccine-naïve individuals. Immune response differences were more pronounced for serogroup C. Differences showed favorable (seroresponse criteria) or comparable (seroprotection criteria) effects for MenACYW-TT in adolescents and adults previously primed with MenACWY-D or MenACWY-CRM. For the risk criteria, rate differences generally showed comparable effects between MenACYW-TT and MenACWY-D or MenACWY-CRM in children, adolescents and adults, while the rate differences for both solicited injection site and systemic reactions favored MPSV4 in older adults. The latter was possibly due to the use of a protein carrier in MenACYW-TT.

Conclusion
The benefit risk-profile of MenACYW-TT in individuals ≥ 2 years is considered favorable relative to comparator licensed vaccines.

Disclosures
David Neveu, MPharm, Sanofi Pasteur (Employee) Marie-Laure Kürzinger, MSc, Sanofi (Employee) Aiying Chen, PhD, Sanofi Pasteur (Employee) Mandeep S. Dhingra, MD, Sanofi Pasteur (Employee)
1244. Assessment of the In Vivo Activity of Human-Simulated Exposure of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) against Enterobacterales (EB) and Pseudomonas aeruginosa (PA) in the Neutropenic Murine Thigh Infection Model
Authors: Gill Christian M , Abdelraouf Kamilia , Nicolau David P 
Published: January 2021

Abstract

Background
Carbapenems are often used for infections due to extended-spectrum-β-lactamase (ESBL) and cephalosporinase (CSase)-producers. As increased carbapenem utilization is associated with the development of carbapenem resistance, antimicrobial stewardship has targeted non-carbapenem options. WCK 4282 (FEP 2 g-TZB 2 g) offers pharmacodynamically optimized TZB exposure and demonstrated potent activity in vitro against ESBL-phenotype isolates. We describe the pharmacodynamics of a WCK 4282 human-simulated regimen (HSR) in the neutropenic murine thigh model.

Methods
19 clinical strains harboring ESBLs or CSase (EB; n=8 and PA; n=4) or serine-carbapenemases (EB; KPC n=4 or OXA-48-like n=3) were tested in vivo. Per CLSI, 19, 18, and 17 isolates were cefepime, ceftolozane/tazobactam, and piperacillin/tazobactam (TZP) non-susceptible, respectively. Thighs of neutropenic, female, CD-1 mice (3 per group) were inoculated with ~107 CFU/mL of bacterial suspension 2 h prior to dosing. Mice received WCK 4282 HSR, FEP HSR, or saline (controls) for 24 h. WCK 4282 HSR and FEP HSR provided plasma exposures in mice that were similar in f%T &gt; MIC and fAUC to FEP-TZB 2 g-2 g and FEP 2 g, respectively, as IV infusions over 1.5 h q8h in humans. Bacterial densities and their changes at 24 h relative to 0 h controls were determined to assess efficacy and reported as mean±SD log10 CFU/thigh.

Results
Bacterial burdens were 5.81±0.36 at 0 h and 9.29±0.88 at 24 h in untreated controls. WCK 4282 produced potent activity against ESBL/CSase producing EB and PA with WCK 4282 MIC ≤ 16 mg/L; mean change in log10 CFU from 0 h was -1.70±0.77, while growth was observed with FEP alone. WCK 4282 produced variable activity against OXA-48-like harboring EB. Against KPC-harboring EB, WCK 4282 produced stasis to growth. Mean Log10 CFU changes are reported in Table 1 and Figure 1.
Table 1. Comparative efficacy of FEP HSR and WCK 4282 HSR by genotypic β-lactamase

Figure 1. Mean Change in log10CFU/thigh for 24 h controls, FEP HSR, and WCK 4282 HSR across the tested MIC distribution.

Conclusion
WCK 4282, a novel TZB containing regimen, resulted in enhance in vitro potency against ESBL/CSase and OXA-48-like producers. Humanized exposures of WCK 4282 produced substantial kill in vivo against ESBL/CSase producers with MICs ≤ 16 mg/L including FEP resistant/TZP non-susceptible PA. These data support further evaluations of WCK 4282 as a carbapenem-sparing regimen for ESBL/cephalosporinase harboring strains.

Disclosures
David P. Nicolau, PharmD, Cepheid (Other Financial or Material Support, Consultant, speaker bureau member or has received research support.)Merck & Co., Inc. (Consultant, Grant/Research Support, Speaker’s Bureau)Wockhardt (Grant/Research Support)