bluuebunny/crossref_metadata_2025_split huggingface dataset:
1235. On the Edge of Tomorrow: Expedited Regulatory Pathways for Anti-Infective Therapies
Authors: Atillasoy Cem , Gourlias Panagiotis 
Published: January 2021

Abstract

Background
The FDA has developed expedited review programs and pathways to increase drug development for products that have a major clinical benefit. These programs include: Fast Track, Orphan Drug Status, Accelerated Approval, Priority Review, Breakthrough Therapy (BTD) and Qualified Infectious Disease Products (QIPD).
Given the heightened awareness of infectious diseases--and emerging global threats, such as resistant bacteria and Ebola—academia and industry have developed and received approval for 88 new infectious disease agents. The objective of this study was to assess the use of expedited review pathways for the 88 anti-infective agents that were approved between 2001-2020.
FDA Expedited Drug Development Programs

Methods
We analyzed the FDA Drug Approval Database entitled, “Compilation of CDER New Molecular Entity (NME) Drug and New Biologic Approvals” for anti-infective therapies that were approved after 2000. Anti-infective therapies were defined as agents that were used to treat or prevent infectious diseases and include antibiotics, antivirals and antifungals. Our analysis focused on a comparison of the percentage of approved anti-infective agents that used each of the aforementioned designations across 2 decades (2001-2010 & 2011-2020). A drug may have one, none, or multiple of these designations.

Results
There were significant differences in the percentage of anti-infective agents approved with priority review, fast track and accelerated approval in 2001-2010 compared to 2011-2020 (See Results Figure 1) BTD and QIDP did not exist until 2012, thus preventing comparisons between decades.

QIDP
• Between 2012-2020, 16 anti-infectives have been approved with QIDP. From 2017-2020, 40% (n=10) of approved anti-infectives had QIDP.
Orphan Drug Status:
• Between 2017-2020, 32% of anti-infectives approved have the orphan drug designation.
Comparison of FDA Expedited Drug Development Programs use between 2001-2010 and 2011-2020

Conclusion
Our findings indicate Priority Review and Fast Track use has increased since 2010 among anti-infective products. Additionally, our analyses indicate that since 2017 there has been increased use of Orphan Drug Status and QIDP. However, there has been limited use of Breakthrough Therapy and Accelerated Approvals. These two pathways should be increasingly considered by academia, industry and the FDA to further expedite innovative anti-infective development.

Disclosures
All Authors: No reported disclosures
1236. Safety and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine (PCV20) in Healthy Infants in the United States
Authors: Senders Shelly , Klein Nicola P , Lamberth Erik , Thompson Allison , Drozd Jelena , Trammel James , Peng Yahong , Giardina Peter , Jansen Kathrin U , Gruber William C , Scott Daniel , Watson Wendy 
Published: January 2021

Abstract

Background
A 20-valent pneumococcal conjugate vaccine (PCV20) is being developed to extend protection against pneumococcal disease beyond that of the 13-valent pneumococcal vaccine (PCV13). This is the first safety and immunogenicity study of PCV20 in healthy infants.

Methods
This randomized, double-blind study enrolled and randomized (1:1) healthy infants ≥ 42 to ≤ 98 days of age to receive a 4-dose series of either PCV20 or PCV13 (control) at 2, 4, 6, and 12 months of age. Local reactions and systemic events were assessed for 7 days after each vaccination; adverse events (AEs) and serious AEs (SAEs) were collected throughout the study. PCV20 immune responses (serotype-specific immunoglobulin G [IgG] and opsonophagocytic activity [OPA]) were measured in sera 1 month after the third infant dose and the fourth dose at 12 months of age.

Results
There were 460 subjects enrolled, with 416 and 391 subjects receiving 3 and 4 doses, respectively. Local reactions and systemic events were predominantly mild to moderate in severity and similar among vaccine groups. There were no related SAEs or deaths reported. PCV20 elicited IgG responses 1 month after the third dose with boosting after a fourth dose. OPA responses were also observed.

Conclusion
PCV20 was well tolerated with a safety profile similar to PCV13. PCV20 elicited immune responses to all 20 vaccine serotypes.

Disclosures
Shelly Senders, MD, Pfizer (Grant/Research Support) Nicola P. Klein, MD, PhD, GSK group of companies (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Protein Science (now SP) (Grant/Research Support)Sanofi Pasteur (Grant/Research Support) Erik Lamberth, MD, Pfizer (Employee) Allison Thompson, MD, Pfizer (Employee) Jelena Drozd, MS, Pfizer (Employee) James Trammel, MS, Pfizer (Employee) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Peter Giardina, PhD, Pfizer (Employee) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)
1238. The Novel Semisynthetic Saponin Adjuvant TQL1055 Enhances the Antibody Response to Pertussis Vaccine with an Improved Tolerability Profile over QS-21
Authors: Buzz Chloe , Ragupathi Govind , Bennett Sean R , Livingston Phil , Farris Eric , Martin Tyler 
Published: January 2021

Abstract

Background
Acellular pertussis vaccines are better tolerated but less immunogenic than older whole cell vaccines. Novel adjuvants may be useful to enhance their immunogenicity. First-generation natural saponins are potent immuno-enhancers but are highly reactogenic. The novel semisynthetic saponin TQL1055 was evaluated for its potential to enhance the immunogenicity of a commercially available acellular pertussis vaccine as part of a National Institute of Allergy and Infectious Disease (NIAID) funded project.

Methods
Groups of 10 female C57BL/6J mice were immunized subcutaneously (SC) with Adacel® (containing 0.5 mcg pertussis toxin antigen) alone or in combination with QS-21 at 20 mcg/dose or TQL1055 at 50 mcg/dose on Days 0 and 28. Serum antibody titer to pertussis antigen was determined by ELISA (Alpha Diagnostics) at Days 0, 28, and 42 and geometric mean titers (GMT) in IU/mL were determined. Body weights were measured serially for 7 days after dose 1.

Results
At 28 days following dose 1, mice receiving TQL1055 had an anti-pertussis toxin IgG GMT of 8492, compared with 2263 in mice receiving QS-21 (p = 0.005). At Day 42, 14 days after dose 2, the GMTs increased to 18719 in the TQL1055 group and 10851 in the QS-21 group (p = 0.0653 vs TQL1055 dose 2; p = 0.6038 vs TQL1055 dose 1). Mice in the Adacel and TQL1055 groups gained weight steadily after dose 1, while mice in the QS-21 group had an average weight loss of 10% from baseline at 3 days after dose 1 (p &lt; 0.0001).
Figure 1: TQL1055 Enhances the Antibody Response to Adacel® (Commercial Acellular Pertussis Vaccine) in C57BL/6J Female Mice

Figure 2: TQL1055 Shows Enhanced Tolerability (measured by decreased weight loss) Compared to QS-21 Following Subcutaneous Injection in C57BL/6J Female Mice

Conclusion
TQL1055 enhanced the antibody response to a commercial acellular pertussis vaccine to a greater degree than QS-21. Additionally, TQL1055 was better tolerated than QS-21, with no weight loss after vaccination. These findings suggested that TQL1055 may improve the performance of acellular pertussis vaccines without an increase in reactogenicity.

Disclosures
Chloe Buzz, BS, Adjuvance Technologies (Employee) Sean R. Bennett, MD PhD, Adjuvance Technologies (Employee) Phil Livingston, MD, Adjuvance Technologies (Consultant, Shareholder) Eric Farris, PhD, Adjuvance Technologies (Employee) Tyler Martin, MD, Adjuvance Technologies (Employee, Shareholder)
1241. PfSPZ Vaccine Administered by Direct Venous Inoculation to Prevent Plasmodium falciparum Malaria is as Safe as Normal Saline – a Meta-analysis of 12 Randomized Controlled Clinical Trials
Authors: Church L W Preston 
Published: January 2021

Abstract

Background
Sanaria’s PfSPZ Vaccine prevents Plasmodium falciparum (Pf) infection transmitted in the field and by controlled human malaria infection. Safety of PfSPZ Vaccine has been demonstrated in 12 randomized, double-blind, placebo-controlled trials (RCT) varying in regimen from 3 to 5 doses over 4 to 20 weeks and in size from 18 to 332 subjects in adults in the US and EU and 5-month to 65-year-olds in 5 countries in sub-Saharan Africa. This study was conducted to analyze solicited adverse event (AE) and laboratory data by random effects meta-analysis.

Methods
PfSPZ Vaccine is composed of radiation-attenuated, aseptic, purified, cryopreserved Pf sporozoites (SPZ) administered by direct venous inoculation (DVI). Normal saline (NS) is always the placebo. Data from all completed RCTs were included as either age &gt; 18 years (n=598) or age 5 months to 17 years (n=641). Any subject receiving at least one dose was included. A random-effects model was used to study vaccine safety and I2 to evaluate heterogeneity. Analysis was performed for any systemic solicited AE and for the most frequently observed AEs and laboratory abnormalities. Sensitivity analyses were performed by removal of trials with zero events to evaluate potential bias.

Results
When examined individually, only 1 trial had a significant difference between PfSPZ Vaccine and NS for any AE (myalgias in adults). In the adult meta-analysis, there was no difference in the random effects risk ratios (RR) for having any vaccine-related AEs (1.40, 95% confidence interval (CI) 0.88-2.28), or for fever (0.75, 0.24-2.35), headache (1.23, 0.74-2.02), fatigue (0.72, 0.19-2.54), or myalgia (1.09, 0.26-4.68). In the pediatric meta-analysis there was no difference between the RR for PfSPZ Vaccine and NS for any AE (0.84, 0.59-1.18) or for fever (1.09, 0.44-2.69). No significant differences in the most common grade 2 or higher laboratory abnormalities – declines in hemoglobin, neutrophil or platelet count – were detected. Sensitivity analysis did not change the results.

Conclusion
There was no difference in risk for AEs or lab abnormalities between PfSPZ Vaccine and NS, indicating that PfSPZ Vaccine administered by DVI was extremely safe and well tolerated in 5-month- to 65-year-olds.

Disclosures
LW Preston Church, MD, FIDSA, Sanaria Inc. (Employee)
1242. Safety and Immunogenicity of Novel 24-Valent Pneumococcal Vaccine in Healthy Adults
Authors: Chichili Gurunadh , Smulders Ronald , Santos Vicki , Cywin Beth , Kovanda Laura , Malinoski Frank J , Sebastian Shite , Siber George R , Malley Rick 
Published: January 2021

Abstract

Background
Invasive pneumococcal disease (IPD) remains prevalent despite the use of conjugate vaccines over the past 20 years. Serotype replacement, limited efficacy for certain vaccine serotypes, and the incomplete coverage of disease in the elderly perpetuate the problem. Novel vaccines with broader serotype coverage are needed. To this end, a novel 24-valent pneumococcal vaccine, ASP3772, was developed based on a multiple antigen-presenting system (MAPS) platform. This platform takes advantage of the high affinity, noncovalent binding between biotin and rhizavidin to create a complex of 24 pneumococcal polysaccharides and a fusion of two pneumococcal proteins.

Methods
Healthy adults aged 18-64 years were randomized into this active-controlled, observer-blinded, dose-escalation study to evaluate the safety, tolerability, and immunogenicity of ASP3772 at three dose levels compared to Prevnar13 (PCV13) (target 30 per dose group). The primary endpoints were safety and reactogenicity. Immunogenicity was evaluated secondarily by measuring serotype-specific immunoglobulin G (IgG) and opsonophagocytic activity (OPA).

Results
Ninety-three subjects received ASP3772 at 1 of 3 doses and 33 received PCV13. Safety and reactogenicity were similar between the ASP3772 and PCV13 arms. Most frequently reported local reactions were tenderness and pain after injection occurring within the first 2 days. Most frequent systemic reactions were fatigue, headache, and myalgia, without a clear dose response. Treatment-emergent adverse events were few and most were mild to moderate in severity. No clinically relevant abnormalities were observed in vital signs, ECGs, and laboratory parameters. Robust IgG and OPA responses were observed for serotypes shared with PCV13, as well as serotypes unique to ASP3772.

Conclusion
ASP3772 vaccine was safe, well tolerated in adults aged 18-64 years, and exhibited robust immunogenicity that extended beyond serotypes shared with PCV13.

Disclosures
Gurunadh Chichili, PhD, Astellas Pharma Inc (Employee) Ronald Smulders, MD, PhD, Astellas Pharma Inc (Employee) Vicki Santos, n/a, Astellas Pharma Inc (Employee) Beth Cywin, n/a, Astellas Pharma Inc (Employee) Laura Kovanda, n/a, Astellas Pharma Inc (Employee) Frank J. Malinoski, MD, PhD, Affinivax Inc (Employee) Shite Sebastian, PhD, Affinivax Inc (Employee) George R. Siber, MD, Affinivax Inc (Consultant, Employee, Shareholder) Rick Malley, MD, Affinivax Inc (Board Member, Consultant, Employee)
98. Clinical and Pharmacoeconomic Impact of Rapid Diagnostic Pneumonia Panel in Critically Ill Patients Admitted with Nosocomial Pneumonia
Authors: Kerr Kathryn H , Vyas Nikunj M , Hou Cindy 
Published: January 2021

Abstract

Background
Rapid identification of causative organisms and tailored antibiotic therapy is essential to improving patient outcomes in critically ill patients with nosocomial pneumonia (NP). The BioFire ® FilmArray ® Pneumonia Panel (BFPP) can identify and semi-quantify the causative organisms via PCR. However, there is limited evidence of its implementation and utility within antimicrobial stewardship program (ASP) in managing NP.

Methods
This was an IRB-approved retrospective pre- and post-interventional study at an acute care hospital. Critically ill patients were included in the intervention group (IG) with a confirmed diagnosis of NP and had BFPP performed. Patients in IG were matched on a 2:1 ratio to a comparator group (CG) who did not receive BFPP. The primary endpoint was clinical cure (CC), defined as: 1) resolution of symptoms and/or leukocytosis; or 2) radiographic improvement; or 3) expression of CC noted by infectious disease physician. Secondary endpoints include time to escalation, de-escalation, or discontinuation of antibiotics, and inpatient mortality (IM). In addition, a pharmaco-economic analysis of the utilization of this panel was conducted.

Results
There were 52 patients evaluated, of which 26 were included in IG and 13 were matched to be included in CG. Demographics were similar between the two groups. No difference in CC was observed between IG and CG (38.5% vs 38.5%, p = 1). However, when evaluating ASP interventions, more patients in IG had de-escalation (53.8% vs 15.4%, p = 0.01) and discontinuation (50% vs 7.7%, p = 0.003) performed compared to CG. No difference was seen in escalation of therapy (34.6% vs 30.8%, NS) and IM (26.9% vs 46.2%, p = 0.27). Time to ASP intervention was quicker by 24 hours in IG vs CG (24 vs 48 hours, p = 0.01). No difference was seen in total cost of therapy between the two groups ($289,500 vs $243,705, p = 0.6). However, cost savings of $31,000 was seen in total cost of ICU care in IG vs CG ($144,000 vs $175,000, p = 0.032).
Figure 1: ASP Intervention

Conclusion
There was no observed impact of BFPP on CC and IM in critically ill patients. However, utilization of BFPP led to faster time to ASP interventions and higher rates of de-escalation and discontinuation of antibiotics. When utilized as part of ASP, BFPP can serve to be a cost-effective option for critically ill patients.

Disclosures
All Authors: No reported disclosures
1245. In Vivo Efficacy of WCK 4282 (High Dose Cefepime [FEP]-Tazobactam [TZB]) Against β-Lactamase-Producing (BLP) Gram-Negative Bacteria in a Neutropenic Murine Pneumonia Model
Authors: Lasko Maxwell J , Abdelraouf Kamilia , Nicolau David P 
Published: January 2021

Abstract

Background
Carbapenems are often used for Extended-Spectrum β-lactamase (ESBL)- and cephalosporinase (AmpC or CMY)-producing infections. Their increased use resulted in the emergence of carbapenem resistance among Gram-negatives, promoting the need of an effective carbapenem-sparing option. WCK 4282 (FEP 2g-TZB 2g) maximizes systemic exposure of TZB and restores FEP activity against piperacillin-tazobactam (TZP) resistant isolates in vitro. Herein we describe the efficacy of WCK 4282 clinical exposures against BLP Enterobacterales (EB) and Pseudomonas aeruginosa (PA) in a murine pneumonia model.

Methods
Clinical isolates (14 EB and 2 PA) with in vitro resistance to FEP, ceftolozane-tazobactam, and TZP (EB isolates) were used. Isolates expressed ESBLs, AmpC/CMY, and/or serine carbapenemases (KPC, OXA-48-like). WCK 4282 MICs were 4-16 and 8-32 mg/L for non-carbapenemase and carbapenemase-producers, respectively. Human-simulated regimens (HSR) of FEP (mimicking human plasma exposure of 2g q8h as a 1.5 h infusion) alone and in combination with TZB (equivalent to 2g q8h as a 1.5 h infusion) were developed in a neutropenic pneumonia model. Treatment mice received FEP or FEP-TZB (WCK 4282) HSR. Control mice were vehicle-dosed. Efficacy was assessed as change in log10CFU/lung at 24 h compared with 0 h controls.

Results
Mean 0 h bacterial density across all isolates was 6.66 ± 0.29 log10CFU/lung and increased at 24 h by 2.48 ± 0.6 and 1.71 ± 1.13 among controls and FEP-treated groups, respectively. Potent WCK 4282 activity was observed against ESBL- and AmpC-harboring EB as well as ESBL- and AmpC-overexpressing PA with WCK 4282 MICs up to 16 mg/L (n=9); mean bacterial reductions were -2.70 ± 0.63 and -2.04 ± 0.18 log10CFU/lung, respectively. WCK 4282 showed variable activity against OXA-48-producing EB (n=3); log10CFU/lung change ranged from -1.2 to 0.28. Against KPC-producers (n=4), WCK 4282 groups grew to 0.53 ± 1.07 log10CFU/lung, ~1.2 log10CFU lower than FEP.

Conclusion
WCK 4282 produced potent in vivo activity against ESBL- and AmpC-harboring Gram-negative isolates and limited activity among serine carbapenamase-producers in a pneumonia model at clinically achievable exposures. Further studies are warranted to delineate WCK 4282’s spectrum of activity and susceptibility breakpoint.

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)
1250. Novel Boronic Acid Transition State Analogs (BATSI) with in vitro inhibitory activity against class A, B and C β-lactamases
Authors: Mojica Maria F , Bethel Christopher , Caselli Emilia , Taracila Magdalena A , Prati Fabio , Bonomo Robert A 
Published: January 2021

Abstract

Background
Catalytic mechanisms of serine β-lactamases (SBL; classes A, C and D) and metallo-β-lactamases (MBLs) have directed divergent strategies towards inhibitor design. SBL inhibitors act as high affinity substrates that -as in BATSIs- form a reversible, dative covalent bond with the conserved active site Ser. MBL inhibitors bind the active-site Zn2+ ions and displace the nucleophilic OH-. Herein, we explore the efficacy of a series of BATSI compounds with a free-thiol group at inhibiting both SBL and MBL.

Methods
Exploratory compounds were synthesized using stereoselective homologation of (+) pinandiol boronates to introduce the amino group on the boron-bearing carbon atom, which was subsequently acylated with mercaptopropanoic acid. Representative SBL (KPC-2, ADC-7, PDC-3 and OXA-23) and MBL (IMP-1, NDM-1 and VIM-2) were purified and used for the kinetic characterization of the BATSIs. In vitro activity was evaluated by a modified time-kill curve assay, using SBL and MBL-producing strains.

Results
Kinetic assays revealed that IC50 values ranged from 1.3 µM to &gt;100 µM for this series. The best compound, s08033, demonstrated inhibitory activity against KPC-2, VIM-2, ADC-7 and PDC-3, with IC50 in the low μM range. Reduction of at least 1.5 log10-fold of viable cell counts upon exposure to sub-lethal concentrations of antibiotics (AB) + s08033, compared to the cells exposed to AB alone, demonstrated the microbiological activity of this novel compound against SBL- and MBL-producing E. coli (Table 1).
Table 1

Conclusion
Addition of a free-thiol group to the BATSI scaffold increases the range of these compounds resulting in a broad-spectrum inhibitor toward clinically important carbapenemases and cephalosporinases.

Disclosures
Robert A. Bonomo, MD, Entasis, Merck, Venatorx (Research Grant or Support)
1251. Prevention of Pneumocystis Pneumonia by Ibrexafungerp in a Murine Prophylaxis Model
Authors: Borroto-Esoda Katyna , Azie Nkechi , Ashbaugh Alan , Cushion Melanie , Angulo David A 
Published: January 2021

Abstract

Background
Pneumocystis pneumonia (PCP) is an opportunistic fungal infection that affects immunocompromised patients. Ibrexafungerp (IBX) is an oral and intravenous antifungal from a novel class of glucan synthase inhibitors, triterpenoids, and has shown activity against Candida, Aspergillus, and PCP in a murine therapy model. We evaluated the ability of IBX to prevent PCP in a prophylaxis model of murine PCP.

Methods
Experiment 1: Balb/c mice (10 mice/group) were infected by intranasal inoculation with Pneumocystis murina, immune-suppressed with dexamethasone in acidified drinking water and treated with 30-, 15- and 7.5 mg/kg, IBX/BID. Control groups treatment included TMP-SMX (50/250 mg/kg QD) and vehicle. After 6 weeks, mice were sacrificed, and prevention was determined by organism burdens (asci and total nuclei). Experiment 2: Balb/c mice were immune-suppressed and infected as in Exp. 1. Treatment groups included: 1) 30 mg/kg BID x 6wk; 2) 30 mg/kg/BID x 6wk followed by cessation of treatment with IBX but with immune-suppression for 3 additional weeks; 3) 15 mg/kg BID 1 week prior and 6 wks after infection and immune suppression; 4) 15mg/kg BID for 8 wks; 5) 15 mg/kg BID for 6 wks then IBX was discontinued but with immune suppression; 6) untreated, vehicle control.

Results
Experiment 1: No P. murina nuclei or asci were observed after 6 weeks of treatment at a dose of 30 mg/kg/BID in the prophylaxis mouse model of PCP, similar to positive control, TMP/SMX. Some nuclei and asci were observed in the lower dose IBX groups. Experiment 2: To investigate whether any P. murina remained after different regimens of prophylaxis, treatment of IBX was withdrawn at both doses for an additional 3 wks of immune suppression to provoke the growth of any remaining fungi. Group 1 showed reduction in total nuclei and asci to undetectable. Group 2 did not result in any recrudescence of infection. Group 3 and 4 showed similar reduction in organism burden. Group 5 was similar to untreated control.

Conclusion
These results demonstrate that 30 mg/kg BID IBX prevented PCP in a murine model. We suggest that IBX could be a viable option for preventing PCP in immunocompromised patients.

Disclosures
Katyna Borroto-Esoda, PhD, SCYNEXIS, Inc. (Employee, Shareholder) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) Alan Ashbaugh, PhD, SCYNEXIS, Inc. (Grant/Research Support) Melanie Cushion, PhD, SCYNEXIS, Inc. (Grant/Research Support) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)