bluuebunny/crossref_metadata_2025 huggingface dataset:
1198. Measurement of Pre-transplant Anti-cytomegalovirus (CMV) Immunoglobulin G Titer to Predict Risk of CMV Infection in CMV-seropositive Kidney Transplant Recipients
Authors: Kirisri Similan , Vongsakulyanon Apirom , Kantachuvesiri Surasak , Bruminhent Jackrapong
Published: January 2021

Background

Although cytomegalovirus (CMV)-seropositive solid organ transplant recipients have a lower risk of CMV infection compared with CMV-seronegative recipients, some patients remain at risk of CMV infection after transplant. Low pre-transplant anti-CMV immunoglobulin G (IgG) titer has been reported as a predictor of CMV infection in CMV-seropositive liver and heart transplant recipients, but this association in CMV-seropositive kidney transplant (KT) recipients has not been explored. We investigated the pre-transplant anti-CMV IgG titer and other CMV infection risk factors in CMV-seropositive KT recipients.

Methods

This retrospective study was conducted on CMV-seropositive KT recipients aged >18 years old at Ramathibodi Hospital during 2017 and 2018. The cumulative incidence of CMV infection was estimated with Kaplan–Meier methodology. The pre-transplant anti-CMV IgG titer was measured with an enzyme-linked fluorescent immunoassay. Risk factors for CMV infection were analyzed with Cox proportional hazards models.

Results

Of the 340 included CMV-seropositive KT recipients (37% female; age [mean±SD]: 43±11 years), 69% and 64% received deceased-donor allograft and induction therapy, respectively. The anti-CMV IgG titer was < 20 and >20 AU/ml in 7.1% and 92.9% of patients, respectively. During a mean follow-up of 14 months, the cumulative incidence of CMV infection was 14.8%, including both asymptomatic CMV infection (69%) and tissue-invasive disease (31%). A pre-transplant anti-CMV IgG titer of < 20 AU/ml was significantly associated with CMV infection in both the univariate analysis (HR, 2.70; 95%CI, 1.21–6.05, [p=0.02]) and the multivariate analysis (HR, 2.98; 95% CI, 1.31–6.77, [p=0.009]). Other significant risk factors of CMV infection included older donor age (HR, 1.03; 95% CI, 1.01–1.06, [p=0.005]), anti-thymocyte induction therapy (HR, 2.90; 95% CI 1.09–7.74, [p=0.033]), and prolonged cold ischemic time (HR, 1.06; 95% CI, 1.02–1.10, [p=0.002]).

Conclusion

A low pre-transplant CMV-specific humoral immunity is independently associated with post-transplant CMV infection in CMV-seropositive KT recipients. The universally available anti-CMV IgG titer test could potentially stratify those at risk and target preventive strategy appropriately.

Disclosures

All Authors: No reported disclosures
1205. Protectin D1 Induced by Clostridium butyricum MIYAIRI 588 Has an Anti-inflammatory Effects on Antibiotic-induced Intestinal Disorder
Authors: Ariyoshi Tadashi , Hagihara Mao , Egushi Shuhei , Aiki Fukuda , Oka Kentaro , Takahashi Motomichi , Mikamo Hiroshige
Published: January 2021

Background

The administration of Clostridium butyricum MIYAIRI 588 (CBM 588) upregulates protectin D1,the anti-inflammatory lipid metabolites, in colon tissue under the antibiotic therapy. However, how CBM 588 induces protectin D1 nor whether the metabolite has anti-inflammatory effects on antibiotic-induced enteritis are unclear. Therefore, we evaluated the effect of CBM 588 on lipid metabolism and protectin D1 on immunological functions in colon tissue.

Methods

Mice were divided into five groups and clindamycin (CLDM), CBM 588 and/or protectin D1 were administered for 4 days (1. Control, 2. CLDM group, 3. CBM 588 group, 4. CLDM plus CBM 588 group and 5. CLDM plus protectin D1 group). After 4 days of administration, mice were reared for an additional 4 days. On day 8, colon tissues were removed to measure lipid metabolites with LC-MS/MS. Also, cytokines, lipid metabolism relative genes, enzymes were measured with qRT-PCR and ELISA.

Results

In the CBM588 treatment group, protectin D1, α-linolenic acid, eicosapentaenoic acid (EPA) and autoxidation product of DHA (docosahexaenoic acid) were significantly increased, compared with CLDM group and control. At the same time, genes expression levels of polyunsaturated fatty acids (PUFAs) receptors, G-protein coupled receptor 120 (GPR120) and a DHA to protectin D1 metabolizing enzyme 15- lipoxygenase (LOX) in colon tissue increased. Il-4 produced by Th2 cells, also increased in CBM588 treated groups even under CLDM co-administration. In addition, similar to CBM 588, protectin D1 administration suppressed mice’s weight loss due to gut inflammation, decreased inflammatory cytokines, while anti-inflammatory cytokine IL-10 and TGF-β1 increased.

PUFAs metabolism cascade induced by CBM 588.

Lipid metabolism relative genes, pro/anti-inflammatory cytokines and body weight.

Conclusion

Our data suggested that CBM 588 stimulated PUFAs metabolism in the intestinal tract, and that PUFAs were signaled to Th2 cells as a ligand of GPR120. It was speculated that the stimulated Th2 cells produced IL4 and activated 15-LOX, resulting in the induction of protectin D1. Also, it became clear that protectin D1 induced anti-inflammatory cytokines in controlling antibiotic-induced gut inflammation. We provide as a new insight that lipid metabolism induction for the treatment of gut inflammatory diseases with CBM 588.

Anti-inflammatory pathway of protectin D1 induced by CBM 588.

Disclosures

Hiroshige Mikamo, M.D, Ph.D, Astellas Pharma Inc. (Grant/Research Support, Speaker’s Bureau)MSD Japan (Grant/Research Support, Speaker’s Bureau)Pfizer Japan Inc. (Grant/Research Support)Sumitomo Dainippon Pharma Co., Ltd (Grant/Research Support, Speaker’s Bureau)
1206. Association of Aging, Frailty and Place of Residence with Skin, Oral and Gut Microbiome Characteristics and Pathogenicity Reservoirs
Authors: Larson Peter J , Oh Julia , Robison Julie , Grady James , Kuchel George
Published: January 2021

Background

Despite their elevated risk for morbidity and mortality from infections, the microbiota of older adults remain understudied. While colonization resistance from resident microflora is a promising means to prevent infections, little is known about pathogenicity reservoirs and colonization resistance in this vulnerable population. Here we study the skin, oral, and gut microbiome dynamics of older adults in both community and Skilled Nursing Facility (SNF) settings, investigating relationships between age, frailty, environment, microbiota, and pathogenicity reservoirs.

Methods

We conducted a longitudinal metagenome survey of 47 adults age 65+ years of age; 22 residents of 3 different SNFs and 25 community dwelling individuals. We performed metagenomic whole genome shotgun sequencing on stool, oral, and skin samples from 8 sites, 1421 total. To correlate clinical and behavioral variables, we measured frailty, collected medical records, and interviewed participants on diet and lifestyle. We also draw comparisons with previous younger cohorts.

Results

• Compared to younger adults, the skin microbiota of older adults was characterized by

◦ High heterogeneity

◦ Decreased stability over time, suggesting increased susceptibility to colonization and pathogenicity

◦ Compositional differences including significantly lower levels of Cutibacterium acnes, with reciprocal increases in Staphylococci, Corynebacteria, and Malassezia

• In older adults, Frailty (Rockwood) was found to have linear correlation with relative abundance of species relevant to infection risk including acnes, staphylococci, streptococci, E. coli, Akkermansia mucinophila, and Enterococcus faecalis.

• The skin, oral, and gut microbiota of SNF residents had substantially elevated virulence factor and antibiotic resistance genes.

Conclusion

To the best of our knowledge, this is largest report to date of the skin metagenome in older adults. We demonstrate distinct and significant differences between cohorts with clinically relevant implications. We believe these results may inform infection control and prevention by increasing our understanding of colonization resistance and pathogenicity reservoirs, as well as advance our knowledge of the relationship between aging, the microbiome, and infections.

Disclosures

All Authors: No reported disclosures
1209. Impact of Respiratory Staphylococcus aureus Abundance on Risk for Ventilator-Associated Pneumonia During Long-Term Care
Authors: Harrigan James J , Abdallah Hatem , Clarke Erik , Lautenbach Ebbing , Reesey Emily , Wernovsky Magda , Tolomeo Pam C , Morawski Zygmunt , Jacob Jerry , Grippi Michael , Kelly Brendan
Published: January 2021

Background

Patients admitted to long-term acute care hospital (LTACH) for ventilator weaning are at high risk for ventilator-associated pneumonia, which may contribute to adverse ventilator-associated events (VAE). Staphylococcus aureus (Sa) is a common cause of VAP. We sought to evaluate the impact of respiratory Sa colonization and bacterial community dominance on subsequent Sa VAP and VAE during long-term acute care.

Methods

We enrolled 83 subjects dependent on mechanical ventilation at LTACH admission, collected endotracheal aspirates, performed 16S rRNA gene sequencing (Illumina HiSeq) and bacterial community profiling (QIIME2). Statistical analysis was performed with R and Stan; mixed effects models were fit to relate the abundance of respiratory Sa on admission to clinically-diagnosed VAP and VAE.

Results

Of the 83 subjects, 8 were diagnosed with Sa pneumonia during the 14 days prior to LTACH admission (“Known Sa”), and 17 additional subjects received anti- Sa antibiotics within 48 hours of admission (“Suspected Sa”); 58 subjects had no known or suspected Sa (“Unknown Sa”). Among the Known Sa group, all 8 had Sa detectable by 16S sequencing, with elevated admission Sa proportional abundance (median 0.36; range 0.0013 - 1). Among the Suspected Sa group, only 7 had Sa detectable by 16S sequencing, with a wide range of admission Sa proportional abundance (median 0; range 0 - 0.96). 25 of 58 subjects in the Unknown Sa group also had detectable respiratory Sa, and a wide range of Sa proportional abundance at admission (median 0; range 0 - 0.93). Incident Sa VAP was observed within 30 days among 2 (25%) of the Known Sa subjects, 0 (0%) of the Suspected Sa subjects, and 3 (5.17%) of the Unknown Sa subjects. VAE was observed within 30 days among 0 (0%) of the Known Sa subjects, 3 (18%) of the Suspected Sa subjects, and 1 (1.7%) of the Unknown Sa subjects. Admission Sa abundance was positively associated with 30-day VAP risk in the Suspected Sa (type S error < 0.001) and Unknown Sa (type S error < 0.001) groups.

Conclusion

Among patients admitted to LTACH for weaning for mechanical ventilation, we observed a high prevalence of respiratory Sa colonization. Respiratory Sa abundance was associated with risk of incident Sa VAP, particularly among subjects without recognized Sa colonization.

Disclosures

All Authors: No reported disclosures
1213. A TRAIL/IP-10/CRP Signature Distinguishes between Viral and Bacterial Infection in Chronic Obstructive Pulmonary Disease Patients
Authors: Paz Meital , Halabi Salim , Shiber Shachaf , Neuberger Ami , Petersiel Neta , Grupper Mordechai , Kirshner Dani , Avni Noa , Stein Michal , Kronenfeld Gali , Shani Liran , Gottlieb Tanya , Lishtzinsky Ynon , Maor Yasmin , Yanai Shirly , Oved Kfir , Eden Eran , Drescher Michael , Paul Michal
Published: January 2021

Background

Challenges in determining the etiology of acute exacerbations of chronic obstructive pulmonary disease (COPD) lead to significant overuse of antibiotics. A new host-response assay that integrates the levels of three proteins (TRAIL, IP-10, and CRP) was shown to exhibit high performance in distinguishing between bacterial and viral disease in two double-blind pediatric validation studies. Here we sought to evaluate its ability to differentiate bacterial from viral infection in adult COPD patients with suspicion of lower respiratory tract infection (LRTI).

Methods

The study population included 492 febrile adult patients prospectively recruited in “Observer”, an EU Horizon 2020 funded study (grant #684589). Patient etiology was determined by majority expert panel based on clinical, laboratory, multiplex PCR, radiological and follow-up data. We compared the expert panel diagnosis with the assay that gives three possible outcomes: viral, bacterial (including viral with bacterial coinfection) or equivocal.

Results

45 out 492 adult patients prospectively recruited with suspicion of LRTI had a medical history of COPD. Of these, 20 cases were assigned as suspected viral infections and 19 as suspected bacterial infections (Figure 1). Antibiotics were prescribed to 19/19 bacterial infections and 16/20 viral infections. The assay correctly classified 19/19 bacterial infections and 12/20 viral infections, with 2 viral cases classified by the assay as bacterial and 6 receiving an equivocal outcome. These data support the assay’s potential to reduce antibiotic overuse from 16/20=80% to 8/20=40% (P=0.01).

FIgure 1: Flow through of COPD patients in prospective performance validation study “Observer”

Conclusion

A new TRAIL/IP-10/CRP signature has potential to significantly reduce antibiotic overuse for patients with suspected LRTI and a history of COPD without missing bacterial infection.

Disclosures

Meital Paz, MD, MeMed Ltd. (Employee) Noa Avni, PhD, MeMed (Employee) Michal Stein, MeMed Ltd. (Employee) Liran Shani, MD, MeMed Ltd. (Employee) Tanya Gottlieb, PhD, MeMed (Employee) Kfir Oved, MD, PhD, MeMed (Employee) Eran Eden, PhD, MeMed (Employee)
1219. Diagnosing vaginal discharge syndrome and its potential impact on clinical practice in a regional hospital in Taiwan
Authors: Huang Sung-Hsi , Hsu Heng-Cheng , Lee Tai-Fen , Fan Hui-Ming , Tseng Chi-Wei , Hsu Hong-Ming , Hung Chien-Ching
Published: January 2021

Background

Vaginal discharges are frequently encountered in clinical practice and usually managed empirically. We aimed to investigate the prevalence of bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) and trichomoniasis among adult women of reproductive age and evaluate the appropriateness of empirical treatment.

Methods

Non-pregnant women between the age of 20 and 49 years who presented with vaginal discharge were prospectively enrolled in a teaching hospital since Oct 2018. Vaginal swabs were collected for determination of Nugent score, culture for Trichomonas vaginalis (TV) and Candida species, and multiplex polymerase chain reaction (PCR) for BV, VVC and TV. Demographics, symptoms, physical findings, and the empirical treatment were recorded.

Results

From Oct 2018 to May 2020, 172 women were included (median age, 37 years). The prevalence of laboratory confirmed BV, VVC, and TV was 21.5% (n=37), 20.3% (35), and 0.6% (1), respectively. Ten (5.8%) women had concurrent BV and VCC. Among 38 women who had bacterial vaginosis or trichomoniasis, only 8 (21.1%) received metronidazole empirically while more than half (11/19, 57.9%) of women who received metronidazole empirically did not have laboratory-confirmed bacterial vaginosis or trichomoniasis. Among 35 women who had candidiasis, 10 (28.6%) received antifungal agents. Antifungal agents were prescribed to more than two thirds (21/31, 67.7%) of women who did not have laboratory confirmed candidiasis. Overall, 58.7% (101/172) of empirical treatment was deemed optimal. Multiplex PCR test has an overall diagnostic accuracy of 86.0% (148/172) as compared to the composite gold standard.

Conclusion

The empirical treatment for vaginal discharge syndrome is suboptimal. Better diagnostic assays have a potential to improve clinical patient care.

Disclosures

All Authors: No reported disclosures
96. Assessing the Impact of the Meningitis/encephalitis Diagnostic Panel on Antimicrobial Stewardship
Authors: Garellek Jonathan , Doan Thien-Ly , Varghese Shawn , Schwartz Rebecca , Rasul Rehana , Donaghy Henry
Published: January 2021

Background

The multiplex polymerase chain reaction (PCR) test for meningitis/encephalitis (ME) is an assay that is available to detect 14 organisms in 2 hours from the cerebral spinal fluid. The primary objective was to assess the clinical impact of this assay on antimicrobial stewardship.

Methods

This is an IRB-approved, retrospective cohort study of a random sample of patients admitted between 7/2015 - 12/2018, stratified by season. A chart review was performed to collect: demographics, microbiology/treatment data, length of stay, hospital readmissions, and mortality. Differences for ME PCR versus culture only were assessed using Chi-square test or Fisher’s exact test. Time to de-escalation of empiric therapy was compared using the log-rank test.

Results

The study consisted of 241 patients, of whom 161 (66.8%) had CSF-PCR testing performed. Mean age was 51.76. There was an even distribution of males and females. Aside from patients with HIV, who were more represented in the standard period, there were no differences by comorbidity. The etiology of meningitis was greater in the PCR compared to the non-PCR group (10.5% vs. 2.5% in PCR and non-PCR respectively). Time to de-escalation of empiric therapy was significantly shorter in the PCR period (median [IQR]: 43.06 [26.9–47.7] vs. 64.62 [37.18–83.33], P< 0.004). Total days of therapy of antibiotics was longer among the PCR group, but not statistically significant (median [IQR] = 4 [1–7] vs. 2 [1–4], P=0.121). Median length of stay was higher in the PCR period compared to the standard group (median [IQR]: 9 [6 - 15] vs. 5.5 [3 - 8.5], P< 0.004). Readmission rates did not differ (PCR 13.7% vs. non-PCR 16.3%, P=0.592). More died during the PCR period (8.6% vs. 3.8%, P=0.16) but this was not statistically significant.

Conclusion

The ME PCR was associated with an earlier time to antibiotics de-escalation. Patients that had the PCR test performed had more days of therapy and longer length of stay, but this is likely due to a higher rate of pathogen diagnosed. There was no association in readmissions. The initiation of rapid diagnostic testing in a healthcare settings has the potential to improve patient outcomes and may help antimicrobial stewardship by shortening the time to de-escalating antimicrobials and offering appropriate targeted therapy.

Disclosures

All Authors: No reported disclosures
1227. Plazomicin Susceptibility Testing using ETEST® MIC for Enterobacterales
Authors: Ying Yun , Armstrong Tom , Blanchard Laurine , Kresken Michael , Zambardi Gilles , Pompilio Marion
Published: January 2021

Background

Plazomicin (PLZ) approved by FDA in June of 2018, is an aminoglycoside class antibacterial indicated for the treatment of adults with complicated urinary tract infections (cUTI) including pyelonephritis caused by Enterobacterales. It is used in patients who have limited or no alternative treatment options, e.g. CRE and MDRO patients. The drug has bactericidal activity, it is active against organisms producing ESBL, Carbapenemase and aminoglycoside-modifying enzymes. The purpose of this study was to compare ETEST® PLZ bioMérieux to the broth microdilution reference method (BMD) for Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca and pneumoniae, Morganella morganii, Providencia stuartii, Proteus mirabilis and vulgaris and Serratia marcescens isolates.

Methods

A total of 598 isolates were tested by ETEST® (PLZ) and BMD at four clinical trial sites.

Isolates were subcultured on tryptic soy or Columbia agar plates supplemented with 5% sheep blood. Suspensions of the isolates were prepared in 0.85% saline, which were used to inoculate BMD and Mueller Hinton agar for ETEST®. Results were read after 16-20 hours incubation at 35°C +2°C in ambient air. QC organisms were tested with each run following CLSI QC guidelines.

Results were analyzed using FDA breakpoints for PLZ (Susceptible <2 µg/mL, Intermediate 4 µg/mL, Resistant >8 µg/mL).

Performance was evaluated using FDA performance criteria, EA and CA (≥ 90%), major error rate (≤3.0%) and very major error rate (≤2.0%).

Results

Conclusion

ETEST® PLZ clinical performance met the FDA acceptance criteria and was found useful for determining Plazomicin MIC of Enterobacterales, including ESBL, CRE (MBL, KPC, Oxa-48), high level AmpC and aminoglycoside resistant strains. Percent susceptibility of Plazomicin is at 80% among the 598 isolates tested, the mode MIC is 0.5 ug/ml as Susceptible.

Disclosures

Tom Armstrong, BS, bioMérieux (Employee) Laurine Blanchard, PhD, bioMérieux (Employee) Michael Kresken, PhD, bioMérieux (Scientific Research Study Investigator, Research Grant or Support) Gilles Zambardi, biomerieux (Employee) Marion Pompilio, BioMérieux (Employee)
1232. Efficacy and Safety of Intravenous Sulopenem Followed by Oral Sulopenem etzadroxil/Probenecid Versus Intravenous Ertapenem Followed by Oral Ciprofloxacin or Amoxicillin-clavulanate in the Treatment of Complicated Urinary Tract Infections (cUTI): Results from the SURE-2 Trial
Authors: Dunne Michael W , Aronin Steven I
Published: January 2021

Background

Sulopenem is a broad-spectrum IV and oral penem antibiotic being developed for the treatment of infections caused by multidrug-resistant bacteria to allow for earlier discharge of hospitalized patients.

Methods

1,395 hospitalized adults with pyuria, bacteriuria, and clinical signs and symptoms of cUTI were randomized to sulopenem IV once daily for 5 days followed by a bilayer tablet of sulopenem-etzadroxil and probenecid bid or ertapenem IV once daily for 5 days followed by either oral ciprofloxacin or amoxicillin-clavulanate bid, depending on susceptibility of the baseline uropathogen. The primary endpoint was overall (clinical and microbiologic) response at Day 21 [Test of Cure (TOC)] in the micro-MITT population.

Results

The sulopenem and ertapenem treatment arms were well-balanced at baseline.

The difference in overall response was driven by a difference in asymptomatic bacteriuria occurring between the end of treatment (EOT) and TOC in the subgroup of patients with a ciprofloxacin susceptible uropathogen at baseline who received ertapenem IV followed by oral ciprofloxacin. No difference in overall response was identified at EOT [86.7% vs 88.9%, sulopenem and ertapenem, respectively; difference, 95% CI: -2.2% (-6.5, 2.2)].

19% of patients remained on ertapenem IV as the baseline pathogen was both resistant to quinolones and ESBL positive; overall response for patients with these resistant pathogens on IV sulopenem who stepped down to oral sulopenem was higher [64/80 vs 55/84 on sulopenem IV/oral and ertapenem IV, respectively; difference, 95% CI: 14.5% (0.8, 27.8)].

Treatment emergent adverse events (all, 14.8% vs 16.1%; related, 6.0% vs 9.2%) and serious adverse events (2.0% vs 0.9%) were similar for patients on sulopenem and ertapenem, respectively.

Overall Response at Test of Cure, micro-MITT Population

Conclusion

Sulopenem followed by oral sulopenem-etzadroxil probenecid was not non-inferior to ertapenem followed by oral step-down therapy for the treatment of cUTI driven by a lower rate of asymptomatic bacteriuria in patients receiving oral ciprofloxacin. Sulopenem, both IV and oral, was well-tolerated; its oral formulation allowed patients with baseline pathogens resistant to both quinolones and β-lactams an opportunity to successfully step down from IV therapy.

Disclosures

Michael W. Dunne, MD, Iterum Therapeutics (Employee, Shareholder) Steven I. Aronin, MD, Iterum Therapeutics (Employee, Shareholder)
1235. On the Edge of Tomorrow: Expedited Regulatory Pathways for Anti-Infective Therapies
Authors: Atillasoy Cem , Gourlias Panagiotis
Published: January 2021

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

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

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 < 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

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 > 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

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

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

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

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 >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

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)