1387. Phase I Study to Evaluate the Safety and Pharmacokinetics (PK) of Single and Multiple Ascending Doses (SAD/MAD) of Intravenous (IV) Minocycline in Healthy Adult Subjects

Abstract Background Carbapenem-resistant Acinetobacter baumannii infections are defined by the WHO as a critical threat. IV minocycline is approved in the United States for treatment of Acinetobacter infections at doses up to 200 mg BID. This study investigated safety and PK of single and multiple doses of IV minocycline, including doses higher than approved in the United States. Methods This was a randomized, double blind, placebo-controlled, SAD/MAD study of 6 doses (100–600 mg) of IV minocycline. Healthy adult subjects received a single dose of minocycline or placebo on Day 1, and 15 doses BID starting on Day 4. Safety was assessed throughout the study. Serial blood and urine samples were collected for PK assessment. Results Sixty-nine healthy subjects were randomized, 49 were included in the PK analysis. No serious adverse events (AEs) occurred; 55 subjects (79.9%) reported study drug-related AEs; dizziness 40 (58.0%) and nausea 34 (49.3%) were the most common. All related AEs were mild except for seven subjects with moderate nausea and/or dizziness. Dosing in the 400 mg cohort was discontinued due to AEs, therefore MAD escalation was stopped. Subsequent cohorts were escalated for SAD and loading dose only. Conclusion Single IV doses of minocycline up to 600 mg were tolerated reasonably well, but the maximum tolerated multi-dose was 300 mg BID. Most common AEs were mild nausea and dizziness with evidence of increasing incidence but not increasing severity with increasing dose. Exposure increased in a dose proportional fashion with exception of the 500 mg dose. The dosage regimen selected for further studies will be a 600 mg loading dose followed by 300 mg BID. Disclosures O. A. Cornely, Innovative Medicines Initiative Joint Undertaking: Grant Investigator, Grant recipient. A. MacGowan, Merck: Commercial grant, Research support; Paratek: Commercial grant, Research support; VenatoRx: Commercial grant, Research support; Bayer: Commercial grant, Research support; Achaogen: Commercial grant, Research support; AiCuris: Collaborator and Commercial grant, Grant recipient and Research support; Polyphor: Commercial grant, Research support; Pfizer: Commercial grant, Research support; Roche: Commercial grant, Research support; Melinta: Industrial partner, Research support; MedImmune (AZ): Industrial partner (IMI), Research support; NIHR England: Grant Investigator, Grant recipient; MRC (UK): Grant Investigator, Grant recipient; Innovate UK: Grant Investigator, Grant recipient. Newton Fund (FCO): Grant Investigator, Grant recipient. S. K. Cammarata, Melinta Therapeutics, Inc.: Employee, Salary. K. Fusaro, Melinta Therapeutics: Employee, Salary. J. S. Loutit, The Medicines Company: Employee and Shareholder, Salary

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Impact of Fatty Acid Supplementation on Cognitive Performance among United States (US) Military Officers: The Ranger Resilience and Improved Performance on Phospholipid-Bound Omega-3’s (RRIPP-3) Study

Nutrients ◽

10.3390/nu13061854 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1854

Author(s):

Bernadette P. Marriott ◽

Travis H. Turner ◽

Joseph R. Hibbeln ◽

Jill C. Newman ◽

Marcie Pregulman ◽

...

Keyword(s):

United States ◽

Controlled Trial ◽

The United States ◽

Military Officers ◽

Krill Oil ◽

Omega 3 ◽

Double Blind ◽

Significant Group ◽

Intention To Treat ◽

Improved Performance

Studies have assessed omega-3 fatty acids and cognitive decline among older adults and cognitive development among children, although less is known about cognitive or neurological effects among young adults. We examined whether omega-3 supplementation from krill oil could improve cognition and resilience among young military officers compared to a control. This double-blind, placebo-controlled trial enrolled 555 officers (mean age 23.4 ± 2.8, 98.6% male) entering the United States (US) Army Infantry Basic Officer Leaders Course (IBOLC) with the intention to complete the US Ranger Course. Volunteer participants consumed eight dietary supplements daily of krill oil containing 2.3 g omega-3 or control (macadamia nut oil) over an approximate 20-week period. Cognitive functioning, resilience, and mood were assessed during a well-rested period at approximately 14 weeks and after a battlefield simulation at 16 weeks. Blood spot samples were collected to monitor compliance and dietary intake was assessed. All hypotheses were tested using both ‘Intention to Treat’ (ITT) and ‘As Per Protocol’ (APP) approaches. Of the 555 randomized individuals, 245 (44.1%) completed the study. No statistically significant group-by-time interactions indicating treatment effect were found on any outcomes. Poor compliance was indicated by lower than expected omega-3 elevations in the treatment group, and may have contributed to a failure to detect a response.

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Efficacy and safety of fremanezumab in patients with migraine and inadequate response to prior preventive treatment: subgroup analyses by country of a randomized, placebo-controlled trial

The Journal of Headache and Pain ◽

10.1186/s10194-021-01232-8 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Egilius L. H. Spierings ◽

Mikko Kärppä ◽

Xiaoping Ning ◽

Joshua M. Cohen ◽

Verena Ramirez Campos ◽

...

Keyword(s):

United States ◽

Czech Republic ◽

Adverse Events ◽

Least Squares ◽

The United States ◽

Inadequate Response ◽

Double Blind ◽

Monthly Average ◽

Preventive Medication ◽

Subgroup Analyses

Abstract Background The FOCUS study evaluated the efficacy of migraine preventive medications across different countries within the same patient population, particularly for patients with difficult-to-treat migraine. These prespecified subgroup analyses evaluated efficacy by country in the FOCUS study of fremanezumab in adults with episodic migraine or chronic migraine and documented inadequate response to 2 to 4 migraine preventive medication classes. Methods Overall, 838 participants were enrolled in the FOCUS study, a randomized, double-blind, placebo-controlled, parallel-group, phase 3b study performed at 104 sites. For 12 weeks of double-blind treatment, patients were randomized (1:1:1) to quarterly fremanezumab, monthly fremanezumab, or matched placebo. The primary efficacy endpoint was the mean change from baseline in monthly average migraine days over 12 weeks of double-blind treatment, evaluated by country in these subgroup analyses. Results Of 14 countries contributing data, the Czech Republic (n = 188/838; 22%), the United States (n = 120/838; 14%), and Finland (n = 85/838; 10%) enrolled the most patients. Changes from baseline in monthly average migraine days over 12 weeks were significantly greater with fremanezumab versus placebo for patients in these countries: Czech Republic (least-squares mean difference versus placebo [95% confidence interval]: quarterly fremanezumab, − 1.9 [− 3.25, − 0.47]; P = 0.009; monthly fremanezumab, − 3.0 [− 4.39, − 1.59]; P < 0.001), the United States (quarterly fremanezumab, − 3.7 [− 5.77, − 1.58]; P < 0.001; monthly fremanezumab, − 4.2 [− 6.23, − 2.13]; P < 0.001), and Finland (quarterly fremanezumab, − 3.0 [− 5.32, − 0.63]; P = 0.014; monthly fremanezumab, − 3.9 [− 6.27, − 1.44]; P = 0.002). Results were comparable for the remaining 9 countries, with the least-squares mean difference versus placebo ranging from – 5.6 to – 2.4 with quarterly fremanezumab and from − 5.3 to − 1.5 with monthly fremanezumab. Incidences of serious adverse events and adverse events leading to discontinuation were low and comparable across countries and treatment groups. Conclusions Monthly and quarterly fremanezumab significantly reduced the monthly average number of migraine days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2 to 4 migraine preventive medication classes. Trial registration ClinicalTrials.gov Identifier: NCT03308968.

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1414. #Vaccine Twitter Influencers: is it Just About Reach and Followers?

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1596 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S714-S715

Author(s):

Jean-Etienne Poirrier ◽

Theodore Caputi ◽

John Ayers ◽

Mark Dredze ◽

Sara Poston ◽

...

Keyword(s):

United States ◽

Social Media ◽

Standard Deviation ◽

Small Proportion ◽

The United States ◽

Research Support ◽

Policy Makers ◽

Media Messages ◽

Social Media Platforms ◽

The Impact

Abstract Background A small number of powerful users (“influencers”) dominates conversations on social media platforms: less than 1% of Twitter accounts have at least 3,000 followers and even fewer have hundreds of thousands or millions of followers. Beyond simple metrics (number of tweets, retweets...) little is known about these “influencers”, particularly in relation to their role in shaping online narratives about vaccines. Our goal was to describe influential Twitter accounts that are driving conversations about vaccines and present new metrics of influence. Methods Using publicly-available data from Twitter, we selected posts from 1-Jan-2016 to 31-Dec-2018 and extracted the top 5% of accounts tweeting about vaccines with the most followers. Using automated classifiers, we determined the location of these accounts, and grouped them into those that primarily tweet pro- versus anti-vaccine content. We further characterized the demographics of these influencer accounts. Results From 25,381 vaccine-related tweets available in our sample representing 10,607 users, 530 accounts represented the top 5% by number of followers. These accounts had on average 1,608,637 followers (standard deviation=5,063,421) and 340,390 median followers. Among the accounts for which sentiment was successfully estimated by the classifier, 10.4% (n=55) posted anti-vaccine content and 33.6% (n=178) posted pro-vaccine content. Of the 55 anti-vaccine accounts, 50% (n=18) of the accounts for which location was successfully determined were from the United States. Of the 178 pro-vaccine accounts, 42.5% (n=54) were from the United States. Conclusion This study showed that only a small proportion of Twitter accounts (A) post about vaccines and (B) have a high follower count and post anti-vaccine content. Further analysis of these users may help researchers and policy makers better understand how to amplify the impact of pro-vaccine social media messages. Disclosures Jean-Etienne Poirrier, PhD, MBA, The GSK group of companies (Employee, Shareholder) Theodore Caputi, PhD, Good Analytics Inc. (Consultant) John Ayers, PhD, GSK (Grant/Research Support) Mark Dredze, PhD, Bloomberg LP (Consultant)Good Analytics (Consultant) Sara Poston, PharmD, The GlaxoSmithKline group of companies (Employee, Shareholder) Cosmina Hogea, PhD, GlaxoSmithKline (Employee, Shareholder)

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Serious Adverse Events Reported with Dietary Supplement Use in the United States: A 2.5 Year Experience

Journal of Dietary Supplements ◽

10.1080/19390211.2018.1513109 ◽

2018 ◽

Vol 17 (2) ◽

pp. 227-248 ◽

Cited By ~ 1

Author(s):

Stephen M. Schmitz ◽

Hector L. Lopez ◽

Douglas Mackay ◽

Haiuyen Nguyen ◽

Paula E. Miller

Keyword(s):

United States ◽

Adverse Events ◽

Dietary Supplement ◽

The United States ◽

Serious Adverse Events ◽

Supplement Use ◽

Dietary Supplement Use

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1047. Global Surveillance: Susceptibility of Ceftolozane–Tazobactam Against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa Isolates Collected From Bloodstream Infections in the United States From 2015 to 2017

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy210.884 ◽

2018 ◽

Vol 5 (suppl_1) ◽

pp. S313-S313

Author(s):

S J Ryan Arends ◽

Dee Shortridge ◽

Mariana Castanheira ◽

Jennifer M Streit ◽

Robert K Flamm

Keyword(s):

United States ◽

Escherichia Coli ◽

Pseudomonas Aeruginosa ◽

Klebsiella Pneumoniae ◽

Bloodstream Infections ◽

The United States ◽

Research Support ◽

Broth Microdilution Method ◽

The Us ◽

Tract Infections

Abstract Background Ceftolozane–tazobactam (C-T) is an antibacterial combination of a novel antipseudomonal cephalosporin and a β-lactamase inhibitor. C-T was approved by the US Food and Drug Administration in 2014 and by the European Medicines Agency in 2015 to treat complicated urinary tract infections, acute pyelonephritis, and complicated intra-abdominal infections. The Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) monitors Gram-negative (GN) isolates resistant to C-T worldwide. In the current study, isolates were collected from patients hospitalized with bloodstream infections (BSIs) from 2015 to 2017 within the United States. Methods A total of 3,377 prevalence-based BSI GN isolates, including Escherichia coli (EC; 1,422), Klebsiella pneumoniae (KPN, 630), and Pseudomonas aeruginosa (PSA; 344), were collected during 2015 to 2017 from 32 PACTS hospitals in the United States. Isolates were tested for C-T susceptibility by CLSI broth microdilution method in a central monitoring laboratory (JMI Laboratories). Other antibiotics tested were amikacin (AMK), cefepime (FEP), ceftazidime (CAZ), colistin (COL), levofloxacin (LVX), meropenem (MEM), and piperacillin–tazobactam (TZP). Antibiotic-resistant phenotypes analyzed (CLSI, 2018) for EC and KPN included carbapenem-R (CR) and non-CR extended-spectrum β-lactamase (ESBL); as well as CAZ-nonsusceptible (CAZ-NS), MEM-NS, and COL-NS PSA. Results Of the 3,377 BSI GN isolates, 3,219 (95.3%) had a C-T MIC ≤ 4 mg/L. The three most prevalent GN species isolated from BSIs were EC (42.1%), KPN (18.7%), and PSA (10.2%). The %S of C-T and comparators for the top three pathogens are shown in the table. C-T showed activity against these isolates with %S of ≥96.0% against all three species. Of the comparators tested, AMK and COL also had high %S against these isolates. Conclusion C-T demonstrated activity against the most prevalent contemporary GN isolates from BSIs in the US. C-T was the only beta-lactam that had ≥96%S against all three species: EC, KPN, and PSA. For PSA, C-T maintained activity (>90%S) against isolates resistant to CAZ, TZP, and MEM. These data suggest that C-T may be a useful treatment for GN BSI. Disclosures S. J. R. Arends, Merck: Research Contractor, Research support. D. Shortridge, Merck: Research Contractor, Research support. M. Castanheira, Merck: Research Contractor, Research support. J. M. Streit, Merck: Research Contractor, Research support. R. K. Flamm, Merck: Research Contractor, Research support.

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Prolonged High Dosage Ataractic Medication in Chronic Schizophrenia

The British Journal of Psychiatry ◽

10.1192/bjp.110.464.61 ◽

1964 ◽

Vol 110 (464) ◽

pp. 61-63 ◽

Cited By ~ 7

Author(s):

D. Rosati

Keyword(s):

United States ◽

Relapse Rate ◽

Chronic Schizophrenia ◽

The United States ◽

Small Study ◽

Double Blind ◽

Mental Hospitals ◽

Therapeutic Results ◽

Near Future

Ataractic drugs have been the mainstay of treatment in schizophrenia for the last eight years. Since their introduction, mental hospitals, in various areas of the United States and in every country, have been able to discharge more patients than they admit. Despite this fact there remains much divergent opinion about the value of these drugs, doubt arising from inconsistent therapeutic results and the relapse rate. Also, some double-blind studies have cast some doubt upon the efficiency of these drugs. We are reporting this relatively small study because we feel that it opens an insight and possibly suggests a method of standardizing treatment in the near future.

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Immunization of Healthy Adult Subjects in the United States with Inactivated Mycobacterium vaccae Administered in a Three-Dose Series

Clinical Infectious Diseases ◽

10.1093/clinids/24.5.843 ◽

1997 ◽

Vol 24 (5) ◽

pp. 843-848 ◽

Cited By ~ 18

Author(s):

C. F. von Reyn ◽

R. D. Arbeit ◽

G. Yeaman ◽

R. D. Waddell ◽

B. J. Marsh ◽

...

Keyword(s):

United States ◽

Healthy Adult ◽

The United States ◽

Mycobacterium Vaccae

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Efficacy and Safety of NVX-CoV2373 in Adults in the United States and Mexico

10.1101/2021.10.05.21264567 ◽

2021 ◽

Author(s):

Lisa M. Dunkle ◽

Karen L. Kotloff ◽

Cynthia L. Gay ◽

German Anez ◽

Jeffrey M. Adelglass ◽

...

Keyword(s):

United States ◽

Controlled Trial ◽

The United States ◽

Efficacy And Safety ◽

Serious Adverse Events ◽

S Protein ◽

Viral Genomes ◽

The United Kingdom ◽

To Receive ◽

Placebo Recipients

BACKGROUND Vaccination using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein antigen has been effective in the prevention of coronavirus disease 2019 (Covid-19). NVX-CoV2373 is an adjuvanted, recombinant S protein nanoparticle vaccine that demonstrated clinical efficacy for prevention of Covid-19 in phase 2b/3 trials in the United Kingdom and South Africa. METHODS This phase 3, randomized, observer-blinded, placebo-controlled trial evaluated the efficacy and safety of NVX-CoV2373 in adults ≥18 years of age in the United States and Mexico during the first quarter of 2021. Participants were randomized in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary end point was vaccine efficacy (VE) against reverse transcriptase-polymerase chain reaction-confirmed Covid-19 in SARS-CoV-2-naive participants ≥7 days after the second dose administration. RESULTS Of the 29,949 participants randomized between December 27, 2020, and February 18, 2021, 29,582 (median age: 47 years, 12.6% ≥65 years) received ≥1 dose: 19,714 received vaccine and 9868 placebo. In the per-protocol population, there were 77 Covid-19 cases; 14 among vaccine and 63 among placebo recipients (VE: 90.4%, 95% confidence interval [CI] 82.9 to 94.6, P<0.001). All moderate-to-severe cases occurred in placebo recipients, yielding VE of 100% (95% CI 87.0 to 100). Most sequenced viral genomes (48/61, 78.7%) were variants of concern (VOC) or interest (VOI), mainly represented by variant alpha/B.1.1.7 (31/35, 88.6% VOC identified). VE against any VOC/VOI was 92.6% (95% CI 83.6 to 96.7). Reactogenicity was mostly mild-to-moderate and transient, but more frequent in NVX-CoV2373 recipients and after the second dose. Serious adverse events were rare and evenly distributed between treatments. CONCLUSIONS NVX-CoV2373 was well tolerated and demonstrated a high overall VE (>90%) for prevention of Covid-19, with most cases due to variant strains. (Funded by the Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; PREVENT-19 ClinicalTrials.gov number, NCT04611802.)

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Time Trends in the Burden of Hospitalizations with Invasive Aspergillosis in the United States, 2004–2013

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.006 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S73-S74

Author(s):

Marya D Zilberberg ◽

Rachel Harrington ◽

James Spalding ◽

Andrew F Shorr

Keyword(s):

United States ◽

Invasive Aspergillosis ◽

Time Trends ◽

The United States ◽

Hospital Length Of Stay ◽

Hospital Charges ◽

Care Utilization ◽

Global Development ◽

The South ◽

Research Support

Abstract Background Invasive aspergillosis (IA) remains a burdensome illness and is associated with substantial mortality. With increasing use of aggressive chemotherapy and immunomodulatory treatments, the prevalence of IA is likely to have grown. However, little is known about the current US burden of IA-related hospitalizations. Methods Using aggregated data available on the interactive website from the Agency of Healthcare Research and Quality’s Health Care Utilization Project Net, we examined the annual volume of IA-related hospitalizations in the United States, based on the presence of the ICD-9-CM codes 117.3, 117.9, and 484.6. Age-adjusted volumes were derived through population incidence calculated using year-specific censal and intercensal US population estimates available from the US Census Bureau. We additionally determined time trends in IA as the principal diagnosis (PD) and its associated charges. Results Between 2004 and 2013, the number of annual hospitalizations with IA grew from 29,774 (standard error, SE 2,425) to 51,870 (SE 2,642), a 74.2% overall increase. This increase was most notable among those aged 45–64 and 65–84 years. Regionally, the South contributed the plurality of the cases (40%), and the Northeast the fewest (17%) with the remainder split evenly between the West and the Midwest. When age-adjusting to year 2013, the growth in the volume of cases was slightly more modest (44.2%), going from 35,968 cases in 2004 to 51,870 in 2013. The proportion of IA hospitalizations in which IA was the PD dropped, from 14.4% in 2004 to 9.3% in 2013. Despite mean hospital length of stay (LOS) decreasing from 13.3 (SE 0.07) in 2004 to 11.5 (SE 0.6) days in 2013, the corresponding mean hospital charges rose from $71,164 (SE $5,248) to $123,005 (SE $9,738). The aggregate US inflation-adjusted hospital charges for IA PD rose from $436,074,445 in 2004 to $592,358,369 in 2013. Conclusion The rate of growth in IA-related hospitalizations in the United States between 2004 and 2013 was substantial. The plurality of cases appears to arise in the South. Despite a moderate decrease in LOS during the time period studied, there was a modest rise in the corresponding hospital charges. The aggregate US annual hospital bill for IA PD discharges is over $0.5 billion. Disclosures M. D. Zilberberg, Astellas Pharma Global Development, Inc.: grant investigator, research support R. Harrington, Astellas Pharma Global Development, Inc.: employee, former employee and salary J. Spalding, Astellas Pharma Global Development, Inc.: employee, salary A. F. Shorr, Astellas Pharma Global Development, Inc.: Consultant and Speaker’s Bureau, consulting fee, research support and speaker honorarium Cidara: consultant, consulting fee Merck: consultant, scientific advisor and Speaker’s Bureau, research support and speaker honorarium

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Dose-Dependent Infectivity of Aseptic, Purified, Cryopreserved Plasmodium falciparum 7G8 Sporozoites in Malaria-Naive Adults

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz410 ◽

2019 ◽

Vol 220 (12) ◽

pp. 1962-1966 ◽

Cited By ~ 4

Author(s):

Matthew B Laurens ◽

Andrea A Berry ◽

Mark A Travassos ◽

Kathy Strauss ◽

Matthew Adams ◽

...

Keyword(s):

United States ◽

Plasmodium Falciparum ◽

Malaria Infection ◽

The United States ◽

Infection Rates ◽

African Countries ◽

Dose Escalation Study ◽

Double Blind ◽

Controlled Human Malaria Infection ◽

Dose Dependent

Abstract Direct venous inoculation of 3.2 × 103 aseptic, purified, cryopreserved, vialed Plasmodium falciparum (Pf) strain NF54 sporozoites, PfSPZ Challenge (NF54), has been used for controlled human malaria infection (CHMI) in the United States, 4 European countries, and 6 African countries. In nonimmune adults, this results in 100% infection rates. We conducted a double-blind, randomized, dose-escalation study to assess the infectivity of the 7G8 clone of Pf (PfSPZ Challenge [7G8]). Results showed dose-dependent infectivity from 43% for 8 × 102 PfSPZ to 100% for 4.8 × 103 PfSPZ. PfSPZ Challenge (7G8) will allow for more complete assessment by CHMI of antimalarial vaccines and drugs.

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