bluuebunny/crossref_metadata_2025 huggingface dataset:
17. Comparative Safety of Antibiotic Therapy for Outpatient Treatment of Uncomplicated Urinary Tract Infections
Authors: Butler Anne M , Durkin Michael , Keller Matthew R , Ma Yinjiao , Powderly William , Olsen Margaret A
Published: January 2021

Background

Urinary tract infection (UTI) is one of the most common indications for outpatient antibiotic prescriptions in otherwise healthy women, yet the comparative safety of antibiotics for empirical therapy is not well established. We compared the risk of adverse drug events by antibiotic treatment regimen among premenopausal women with uncomplicated UTI.

Methods

Using the IBM MarketScan Commercial Database (2006–2015), we identified healthy, non-pregnant women aged 18–44 who were diagnosed with UTI and prescribed a same-day antibiotic with activity against common uropathogens. Patients were followed for outcomes with varying follow-up periods: 3 days (anaphylaxis), 14 days (acute renal failure, skin rash, urticaria/hives, nausea/vomiting, abdominal pain), 30 days (vaginitis/vulvovaginal candidiasis, non-C. difficile diarrhea) and 90 days (C. difficile diarrhea, pneumonia, tendinopathy, retinal detachment). We estimated propensity score-weighted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models.

Results

Of 1,140,602 eligible women, the distribution of antibiotic receipt was fluoroquinolones (44%), trimethoprim-sulfamethoxazole (TMP/SMX) (28%), nitrofurantoin (24%), narrow-spectrum β-Lactam / β-Lactamase inhibitor combinations (“β-Lactams”) (3%), broad-spectrum β-Lactams (1%) and amoxicillin/ampicillin (1%). Of two first-line agents, we observed higher risk of outcomes among TMP/SMX vs. nitrofurantoin initiators: acute renal failure (HR 2.46, 95% CI 1.46–4.14), skin rash (HR 2.43, 95% CI 2.13–2.77), urticaria (HR 1.35, 95% CI 1.18–1.56), nausea/vomiting (HR 1.19, 95% CI 1.10–1.29) and abdominal pain (HR 1.14, 95% CI 1.09–1.19). Compared to nitrofurantoin, non-first-line agents (fluoroquinolones, broad-, and/or narrow-spectrum β-Lactams) were associated with higher risk of acute renal failure, skin rash, nausea/vomiting, abdominal pain, vaginitis/vulvovaginal candidiasis, diarrhea (C. difficile & non-C. difficile), pneumonia and tendinopathy.

Conclusion

The risk of adverse drug events differs widely by antibiotic agent, with substantial differences in first-line agents. Understanding antibiotic safety is critical to prevent suboptimal antibiotic prescribing and reduce adverse events.

Disclosures

Margaret A. Olsen, PhD, MPH, Merck (Grant/Research Support)Pfizer (Consultant, Grant/Research Support)
18. Durations of Antibiotic Therapy and Factors Associated with Longer Than Recommended Durations for Common Ambulatory Infections in an Integrated Healthcare System
Authors: Deida Axel Vazquez , Shihadeh Katherine C , Aragon Deborah , Knepper Bryan C , Jenkins Timothy C
Published: January 2021

Background

Duration of antibiotic therapy is an important focus for antibiotic stewardship, but the extent and drivers of excessive durations are not well understood. This project aimed to describe durations of therapy prescribed for common infections across the ambulatory care settings of an integrated healthcare system and identify factors associated with longer than recommended durations.

Methods

This was a retrospective, cross-sectional evaluation conducted from July 1, 2018 to June 30, 2019. We identified antibiotic prescriptions for adults age 18 years or older presenting to a Denver Health ambulatory care facility (urgent care, emergency department, family medicine clinic, or internal medicine clinic) for an infection with a recommended duration of therapy of 5 days or less based on institutional guidance. Infections included purulent and non-purulent cellulitis, uncomplicated subcutaneous abscess, acute bacterial sinusitis (ABS), acute otitis media (AOM), community acquired pneumonia, cystitis, and pyelonephritis treated with an indicated fluoroquinolone. Prescriptions for more than 5 days were classified as longer than recommended. We evaluated whether the following factors were associated with longer than recommended prescriptions: location of visit, type of infection, patients’ age, race/ethnicity, sex, infection type, and prescribing provider type

Results

5331 prescriptions met inclusion criteria. Of those, the duration of therapy was longer than recommended for 2095 (39%) (Table 1). Durations varied significantly across locations (p< 0.0001). In the sub-group analysis family medicine clinics had the highest proportion of longer than recommended durations (46%). Durations also varied significantly by type of infection. For cellulitis, ABS, and AOM, the duration was longer than recommended in 50%, 54%, and 75% of cases, respectively. Other factors associated with longer than recommended durations included male sex (p< 0.0001) and prescriptions by advanced practice providers (p = 0.0008).

Table 1: Antibiotic Duration of Therapy for Common Outpatient Infections

Conclusion

Care locations, infection types, and both patient and prescriber factors were associated with longer than recommended prescriptions suggesting specific opportunities to prevent excessive durations of therapy.

Disclosures

All Authors: No reported disclosures
19. A Global Point Prevalence Survey of Antimicrobial Use in Neonatal Intensive Care Units
Authors: Prusakov Pavel , Goff Debra A , Wozniak Phillip , Sanchez Pablo J
Published: January 2021

Background

Antimicrobials are one of the most commonly used medications in the NICU. We aimed to gather baseline global data on antimicrobial use to facilitate subsequent antimicrobial stewardship efforts.

Methods

We conducted a one-day global NICU point prevalence study on July 1, 2019 with a 30-day follow up. Data collection included patient demographics, antimicrobial therapy, site location, antimicrobial stewardship (AS) practices as well as the duration of antimicrobial therapy and in-hospital mortality were recorded.

Results

Eighty-one NICUs from twenty-eight different countries identified 2,163 admitted patients of which 570 (26%) were prescribed at least one antimicrobial. Three NICUs did not have any patients on antimicrobial therapy, all had less than 20 patients admitted. Level 3 and Level 4 NICUs comprised 51% and 48% respectively. Delivery units comprised 74%, the rest were referral centers. AS programs were in place in 62% of the hospitals and 47% of the units had NICU specific initiatives. Patients were on average 32.5 weeks gestational age (+/-5.3 SD), with birth weight of 1976 grams (+/- 1022 SD), and were 32 days (+/-65 SD) postnatal age at the time of the study.

Antibiotics were the most frequently used medication in 92% of patients with 931 antibiotics prescribed on the assessment day. Hospitals with any NICU AS initiative had significantly lower rates of antibiotic utilization compared to NICUs without AS (21% and 32%; p-value: < 0.01). Of those on antibiotic therapy, ampicillin, gentamicin and amikacin were prescribed to 41%, 34%, and 21% of patients respectively. When only definitive treatment was evaluated, vancomycin, amikacin, and meropenem were the highest prescribed antibacterial agents at 25%, 19%, and 19% respectively. At the initial assessment, study participants indicated either 3 or 7 days (37% and 26%) for planned duration. Actual treatment duration for empiric and definitive treatment, was 7 and 14 days (29% and 19%) When comparing patients who had an established treatment course at the time of the initial assessment, the final length of treatment for culture negative sepsis was 7 (IQR:5–10) and culture positive sepsis was 11 days (IQR:10–14; p-value: 0.07).

Conclusion

Benchmarking global antimicrobial use is crucial for improving NICU-AS practices.

Disclosures

Pavel Prusakov, PharmD, Merck (Research Grant or Support) Debra A. Goff, PharmD, Merck (Research Grant or Support)
23. Regional Variation in Outpatient Antibiotic Prescribing in a Commercially-insured Population, United States, 2017
Authors: Bizune Destani J , Palms Danielle , King Laura M , Bartoces Monina , Link-Gelles Ruth , Hicks Lauri , Fleming-Dutra Katherine E
Published: January 2021

Background

Studies have shown that the Southern United States has higher rates of outpatient antibiotic prescribing compared to other regions in the country, but reasons for this variation are unclear. We aimed to determine whether the regional variability in outpatient antibiotic prescribing for respiratory diagnoses can be explained by differences in patient age, care setting, comorbidities, and diagnosis in a commercially-insured population.

Methods

We analyzed the 2017 IBM® MarketScan® Commercial Database of commercially-insured individuals aged < 65 years. We included visits with acute respiratory tract infection (ARTI) diagnoses from retail clinics, urgent care centers, emergency departments, and physician offices. ARTI diagnoses were categorized as: Tier 1, antibiotics are almost always indicated (pneumonia); Tier 2, antibiotics are sometimes indicated (sinusitis, acute otitis media, pharyngitis); and Tier 3, antibiotics are not indicated (asthma, allergy, bronchitis, bronchiolitis, influenza, nonsuppurative otitis media, viral upper respiratory infections, viral pneumonia). We calculated risk ratios and 95% confidence intervals (CI) stratified by US Census region and ARTI tier using log-binomial models controlling for patient age, comorbidities (Elixhauser and Complex Chronic Conditions for Children), and setting of care, with Tier 3 visits in the West, the strata with the lowest antibiotic prescription rate, as the reference for all strata.

Results

A total of 100,104,860 visits were analyzed. In multivariable modeling, ARTI visits in the South and Midwest were highly associated with receiving an antibiotic for Tier 2 conditions vs. patients in other regions (Figure 1).

Figure 1. Multivariable model comparing risk of receiving an antibiotic for an ARTI by region and diagnostic tier in urgent care, retail health, emergency department, and office visits, MarketScan® 2017, United States

Conclusion

Regional variability in outpatient antibiotic prescribing for Tier 2 and 3 ARTIs remained even after controlling for patient age, comorbidities, and setting of care. It is likely that this variability is in part due to non-clinical factors such as regional differences in clinicians’ prescribing habits and patient expectations. Targeted and enhanced public health stewardship interventions are needed to address cultural factors that affect antibiotic prescribing in outpatient settings.

Disclosures

All Authors: No reported disclosures
27. The Membrane Antimicrobial Peptide Defense (MadRS) System Orchestrates Resistance Against Antibiotics and Host Innate Immune Peptides in enterococcus Faecalis
Authors: Miller William R , Khan Ayesha , Erickson Samuel G , Pettaway Cedric H , Rios Rafael , Cruz Melissa R , Dinh An Q , Diaz Lorena , Garsin Danielle A , Arias Cesar A
Published: January 2021

Background

Enterococci have evolved a network of two component-signaling systems (TCS) to evade killing by cationic antimicrobial peptides (AP) of the host innate immune response. Activation of these pathways can also lead to cross-resistance to AP-like antibiotics such as daptomycin (DAP), complicating treatment of severe enterococcal infections. Our previous work implicated the MadRS (formerly YxdJK) TCS in resistance to DAP. In this work, we show that the MadRS system regulates a network of membrane defense proteins that provide targeted resistance to killing by LL-37.

Methods

We performed a global transcriptional analysis comparing wild type (WT) E. faecalis OG1RF and an OG1RF derivative possessing a mutated allele of the madS gene that activates the MadRS system (OG1RFmadSA202E). Selected genes identified in this analysis were knocked out using a CRISPR-cas9 gene editing system and confirmed by sequencing. Antibiotic minimum inhibitory concentrations (MIC) were determined using gradient diffusion strips. LL-37 killing assays were performed in triplicate in RPMI+5% LB broth. Caenorhabditis elegans assays were performed in triplicate, and representative results are shown.

Results

Analysis of the MadRS regulon revealed a significant upregulation of a network of gene targets, including madLM (formerly yxdLM, involved in bacitracin resistance), madEFG, the dlt operon, salA, and EF2211 (Fig 1). The madSA202E allele was associated with increased bacterial survival on exposure to LL-37, while the madEFG deletion mutant was more susceptible to killing (Fig 2A). Deletion of madLM decreased bacitracin MICs, but did not alter survival on exposure to LL-37. In C. elegans, inactivation of the MadRS system by deletion of the madR response regulator resulted in attenuation as compared to WT OG1RF. The effect was reversed by complementing with wild-type madR on a plasmid (Fig 2B). The attenuation effect of the mutant was abolished in pmk-1 knockout worms, which lack the ability to produce innate immune peptides (Fig 2C).

Figure 1

Figure 2

Conclusion

The MadRS system plays an important role in mediating resistance to AP both in vitro and in vivo. The novel ABC-transporter MadEFG is likely to play a major role in preventing enterococcal killing by the human cathelicidin LL-37.

Disclosures

William R. Miller, MD, Entasis Therapeutics (Scientific Research Study Investigator)Merck (Grant/Research Support)Shionogi (Advisor or Review Panel member) Cesar A. Arias, M.D., MSc, Ph.D., FIDSA, Entasis Therapeutics (Scientific Research Study Investigator)MeMed (Scientific Research Study Investigator)Merck (Grant/Research Support)
31. Post-ebola Syndrome Presents with Multiple Overlapping Symptom Clusters: Evidence from an Ongoing Cohort Study in Eastern Sierra Leone
Authors: Himmelfarb Sarah Talia , Bond Nell , Okoli Adaora , Schieffelin John , Shaffer Jeffrey , Samuels Robert J , Engel Emily J
Published: January 2021

Background

Since the outbreak of Ebola Virus Disease (EVD) in West Africa from 2013–2016, a large cohort of survivors with persistent health complaints has emerged. This constellation of issues is termed post-Ebola syndrome. Here we characterize the symptoms and physical exam findings of this syndrome in a cohort of survivors from Sierra Leone 2.6 years after resolution of disease.

Ebola survivors present with clusters of symptoms that represent sub phenotypes of post-Ebola syndrome

Methods

Potential survivor participants in Eastern Sierra Leone were identified and recruited through the Sierra Leone Association of Ebola Survivors. Household contacts of survivors were identified by enrolled survivors. Both groups were administered a questionnaire assessing self-reported symptoms. A physical exam was performed by a limited number of trained providers. Symptoms were then compared using hierarchical clustering. Statistical analysis of the correlations between clusters was conducted using conditional logistic regression. Both SPICE and principal component (PCA) analyses were performed to explore the relationships between symptom clusters.

Results

Between March 2016 and January 2019, 375 Ebola survivors and 1040 contacts were enrolled. At enrollment, Ebola survivors of all age groups reported significantly more symptoms than their contacts in all categories. Six symptom clusters were identified representing distinct organ systems. SPICE revealed 2 general phenotypes: with or without rheumatologic symptoms. Clusters including rheumatologic symptoms were correlated with one another (r = 0.63) but not with other clusters (r < 0.35). Ophthalmologic/auditory symptoms were moderately correlated with the non-rheumatologic clusters (r > 0.5). Interestingly, psychologic/neurologic, cardiac/GI and constitutional clusters correlated with one another (r > 0.6) p < 0.0001 in all cases. The symptom clusters were then mapped onto a PCA. Each symptom cluster separated from the remainder along PC1, particularly the phenotypes with rheumatologic symptoms.

Conclusion

This study presents an in-depth characterization of post-Ebola syndrome in Sierra Leonean survivors. The interrelationship between symptom clusters indicates that post-Ebola syndrome is a heterogeneous disease. The phenotypes identified may have unique mechanisms of pathogenesis, and require distinct therapies.

Disclosures

John Schieffelin, MD, MSPH, Wolters-Kluwer (Independent Contractor)
33. Concerning Trends of Pediatric Leprosy in Minas Gerais, Brazil and Associations with Number of Municipality Medical Facilities
Authors: Landay Taylor , Clennon Julie A , Ferreira José A , Fraga Lucia A , Grossi Maria Aparecida F , Fairley Jessica K
Published: January 2021

Background

Leprosy in children under 15 years of age, and in particular, the presence of leprosy grade 2 disability (G2D) in children, signifies ongoing transmission and the need for improved surveillance. Our objective was to describe the epidemiology of pediatric leprosy in Minas Gerais, Brazil and to explore associations with access to medical facilities.

Methods

A cross-sectional study was conducted using data from the Brazilian Notifiable Diseases Surveillance System (SINAN) from 2002–2017. Incident cases were included if they resided in a municipality with both adult and pediatric cases. Municipalities were divided by the number of medical facilities per municipality: < 5, 5–17, and 18 or higher. Analyses compared pediatric cases across two time periods (2002–2009 and 2010–2017) and number of medical facilities / municipality using chi-square, t-tests, and logistic regression.

Results

A total of 27,725 cases were reported with 1,611 under 15 years of age. Overall incidence declined from 34.8 per 100,000 to 13.6 per 100,000 during the study period with pediatric incidence declining from 2.6 per 100,000 to 0.8 per 100,000. Time period 2 (TP2) showed an increase in the proportion of pediatric G2D (2.58% vs 1.91%, p < 0.0001) when compared to time period 1 (TP1). Mean age of diagnosis in children was younger in TP2 then in TP1 (10.06 vs 10.43, p=0.02). In 2017, the pediatric incidence in municipalities with the fewest medical facilities was 0.95 per 100,000 compared to 0.23 per 100,000 in municipalities with > 5 facilities (p=0.009). There was significantly higher odds of disability at diagnosis (grades 1 and 2) in pediatric cases residing in municipalities with < 5 medical facilities (aOR 1.88; 95% CI 1.37–2.59), adjusted for age and sex. See map (Fig 1).

Figure 1. Cases of Pediatric Disability By Number of Municipality Medical Facilities from 2002–2017 (White areas without reported pediatric leprosy)

Conclusion

The increasing proportion of G2D in children in the second half of the study period despite declining incidence suggest occult infections among children and adults alike in Minas Gerais. Furthermore, the average age of diagnosis in children should increase, not decrease, if M. leprae transmission was truly declining. Lastly, the association between fewer municipality health facilities and increased disability suggest barriers to timely diagnosis and a critical area of focus for research into access to healthcare and leprosy risk.

Disclosures

All Authors: No reported disclosures
38. Predicting stenotrophomonas Maltophilia bloodstream Infections (BSI) in the Hematologic Malignancy Population
Authors: Karaba Sara M , Amoah Joe , Cosgrove Sara E , Tamma Pranita D
Published: January 2021

Background

Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred treatment for S. maltophilia BSI. Hematologic malignancy patients are at increased risk of S. maltophilia BSI but because of the TMP-SMX adverse event profile, this agent is not routinely included in empiric treatment regimens. We sought to identify risk factors for S. maltophilia BSI in hematologic malignancy patients to guide empiric treatment decisions in this population.

Methods

Inpatients ≥ 12 years at Johns Hopkins Health System hospitals between 7/1/16-12/1/19 with a hematologic malignancy and/or stem cell transplant (SCT) within 12 months were included. Cases were patients with S. maltophilia BSI and controls were patients with BSI from Gram-negative organisms other than S. maltophilia. Demographics, pre-existing medical conditions, antibiotic use (including prophylaxis) in the previous 3 months, and hospitalization in the previous 3 months were compared between cases and controls using non-parametric methods and multivariable logistic regression.

Results

There were 20 cases and 105 controls. Cases and controls were similar in terms of age, sex, type of underlying malignancy, proportion with recent SCT, absolute neutrophil count, (ANC), central venous catheter, and severity of illness. Cases were more likely to have received ≥ 72 hours of a carbapenem within the preceding 3 months, controlling for age, recent SCT, ANC, and central venous catheter (OR=3.11, 95% 1.05–9.16, p=0.04). There were no significant differences in prior cefepime or piperacillin/tazobactam use in the preceding 3 months between cases and controls.

Conclusion

Hematologic malignancy patients who received ≥ 72 hours of carbapenem therapy, but not other broad spectrum antibiotic use within the previous 3 months were more likely to be infected with S. maltophilia BSI. Identifying patients at high risk for S. maltophilia BSI can ensure early, appropriate empiric therapy – ultimately improving clinical outcomes.

Disclosures

All Authors: No reported disclosures
39. Comparative One-year Outcomes of Invasive staphylococcus Aureus infections Among Persons with and Without Drug Use in an Urban West Coast Cohort
Authors: Appa Ayesha Ashley , Adamo Meredith , Le Stephenie , Davis Jennifer , Winston Lisa Gail , Doernberg Sarah B , Chambers Henry , Martin Marlene , Coffin Phillip , Jain Vivek
Published: January 2021

Background

Persons who use drugs (PWUD) face substantial risk from invasive Staphylococcus aureus infections but have important demographic and clinical differences from persons without drug use (non-PWUD). Despite this, limited data exist comparing S. aureus infection outcomes in PWUD vs. non-PWUD; these data are needed to inform interventions to optimize care for this vulnerable population.

Methods

We identified adults hospitalized from 2013–2018 at two academic hospitals in San Francisco with S. aureus bacteremia or ICD-coded diagnoses of endocarditis, epidural abscess, or vertebral osteomyelitis with compatible S. aureus culture. Via structured chart review, we compared the following among PWUD vs. non-PWUD: clinical and substance use features, adjusted odds of antibiotic completion, and one-year infection-free survival using a multivariate Cox proportional hazards model adjusted for age/race, housing, comorbidities, and MRSA.

Results

Of 963 hospitalizations for invasive S. aureus infections in 946 patients, 372/963 (39%) occurred in PWUD. Among PWUD, heroin (198/372, 53%) and methamphetamine use (185/372, 50%) were common (Table 1). Bacteremia occurred in 82% of hospitalizations. PWUD vs. non-PWUD had higher proportions of MRSA (48% vs. 31%) and invasive infections: 20% vs. 12% with endocarditis, 25% vs. 11% with epidural abscess, and 28% vs. 13% with vertebral osteomyelitis (all p< 0.001). PWUD had more self-directed (“AMA”) discharges, and most using opioids did not receive methadone or buprenorphine (Table 2). PWUD completed antibiotic courses less often (70% vs. 87%; p< 0.001) and had 2.9-fold higher adjusted odds of incomplete treatment (95% CI:1.7–5.0). One-year mortality was lower in PWUD (18% vs. 30%), but one-year readmission for ongoing/recurrent infection was far higher (28% vs. 14%; HR 1.9 [95% CI:1.3–2.9], Figure 1).

Table 1: Demographic, Clinical, and Substance Use Characteristics

Table 2: Care Delivery, PWUD vs. non-PWUD

Figure 1: One-year Infection-free survival in persons who use drugs (PWUD) vs. non-PWUD

Conclusion

PWUD had higher proportions of S. aureus vertebral osteomyelitis, epidural abscess, and endocarditis than non-PWUD, lower odds of treatment completion, and greater risk of infection persistence/recurrence at one year. Among PWUD, opioid and stimulant use were common and undertreated. New patient centered models of care that deliver synchronized S. aureus infection and substance use disorder therapy are urgently needed.

Disclosures

All Authors: No reported disclosures
46. Tacrolimus Increases Susceptibility to Secondary Infection in a Mouse Model
Authors: Miller-Handley Hilary , Kinder Jeremy , Pham Giang , Way Sing Sing
Published: January 2021

Background

Transplant acceptance requires life-long pharmacological intervention that broadly suppresses recipients’ immunity in order to prevent rejection of foreign graft. In turn, non-specific immune-suppression in these patients is also associated with increased risk of infection from opportunistic pathogens. Currently our knowledge on the effects immune suppressive therapies on adaptive immune components response in patients is limited

Methods

To investigate this we established a mouse model of post-transplant immune suppression therapy, using tacrolimus. To dissect the effects of tacrolimus on infection susceptibility, tacrolimus-treated mice were infected with a virulent strain of recombinant Listeria monocytogenes (Lm) expressing model antigens. Infection with this transgenic strain of Lm transforms these model antigens into surrogate Lm antigens and allows tracking of pathogen-specific T-cells using MHC tetramer staining.

Results

Here we show, tacrolimus treatment triggered increased susceptibility to secondary, but not primary Lm infection with increased bacterial burden in the liver and spleen tissues. Increased susceptibility during secondary infection paralleled dampened functional activation of Lm-specific CD8+ T cells as indicated by diminished in vivo cytolytic activity. Interestingly, when tacrolimus treatment was initiated only during primary or during secondary infection susceptibility to infection was overturned as both groups of mice had lower bacterial burden in target tissues. This suggests that while tacrolimus treatment does not negatively impact primary immune response, it may dampen the formation of CD8+ T cell memory.

Conclusion

Further studies will investigate the long-term durability of blunted pathogen-specific memory and CTL activity triggered by tacrolimus treatment after cessation of therapy. These findings will allow more defined prediction of patient risk of infection allowing for a personalized prophylaxis regimen.

Disclosures

All Authors: No reported disclosures
3. A Review of the Clinical Development of MenACWY-TT, a Quadrivalent Meningococcal Vaccine Conjugated to Tetanus Toxoid, in Adolescents
Authors: Peyrani Paula , Webber Chris , Burman Cindy , Balmer Paul , Perez John L
Published: January 2021

Background

As a peak in meningococcal disease often occurs during adolescence, meningococcal vaccination programs are available for this age group in various regions across the globe. Quadrivalent meningococcal (MenACWY) conjugate vaccines are being incorporated in an increasing number of programs in response to changing meningococcal serogroup epidemiology. MenACWY-TT (Nimenrix®) is a MenACWY conjugate vaccine available in the European Union and 50 other countries for preventive vaccination of serogroup A, C, W, and Y disease (Figure 1). MenACWY-TT is licensed in some countries as a 2-dose primary series in individuals as young as 6 weeks of age, while a single dose may be given to previously unvaccinated individuals ≥ 6 months of age, adolescents, and adults. Here, we provide an overview of the 3 primary and 5 extension studies evaluating the clinical development of MenACWY-TT in adolescents (Table 1).

Figure 1. Global Registration Status of MenACWY-TT (Nimenrix®) in Adolescents

Table 1. Pivotal Clinical Studies of MenACWY-TT (Nimenrix®) Supporting Licensure in Adolescents

Methods

Immunogenicity and safety data from these 8 clinical studies are summarized.

Results

Across studies, MenACWY-TT antibody responses against all vaccine serogroups were comparable to those of other MenACWY vaccines 1 month post vaccination (Table 1). Antibody responses to MenACWY-TT persisted for up to 10 years in those vaccinated during adolescence. A MenACWY-TT booster given 10 years after primary meningococcal vaccination in early childhood or adolescence elicited robust antibody responses. MenACWY-TT had an acceptable safety profile, with reactogenicity events most commonly reported. Reactogenicity profiles with MenACWY-TT booster were similar to those seen after primary MenACWY-TT.

Conclusion

The MenACWY-TT clinical study program demonstrated the immunogenicity and safety of primary and booster dosing in adolescents. Immune responses persisted through 10 years after primary vaccination.

Funding

Pfizer.

Disclosures

Paula Peyrani, MD, Pfizer Inc (Employee, Shareholder) Chris Webber, MD, Pfizer Inc (Employee, Shareholder) Cindy Burman, PharmD, Pfizer Inc (Employee, Shareholder) Paul Balmer, PhD, Pfizer Inc (Employee, Shareholder) John L. Perez, MD, MA, Pfizer Inc (Employee, Shareholder)
5. Observational Study of Routine Use of 9-Valent Human Papillomavirus Vaccine: Safe in More Than 140,000 Individuals
Authors: Hansen John , Yee Arnold , Lewis Ned , Li Se , Velicer Christine , Saddier Patricia , Klein Nicola P
Published: January 2021

Background

Nine-valent human papillomavirus (HPV) vaccine (9vHPV vaccine, Gardasil®9) was licensed in the US in Dec-2014. Using a self-controlled risk interval design, we conducted a post-licensure retrospective cohort study within Kaiser Permanente in Northern California (KPNC) to assess 9vHPV safety following routine administration.

Methods

We included KPNC members 9-years or older who received 9vHPV as their first dose of HPV vaccine between Oct-2015 and Sep-2017. Post-vaccination emergency and hospitalization events were compared during risk intervals (days 1–60 and 0–14) with later self-comparison intervals using conditional logistic regression, following all 9vHPV vaccine doses combined, and by dose. We investigated significant findings by assessing post-vaccination timing and medical record reviews. We evaluated and reviewed medical records for all day 0 allergic reaction and syncope events, and all deaths during the study. An independent Safety Review Committee reviewed potential safety signals.

Results

We studied 140,628 9vHPV-vaccinated individuals, including 69,027 (49%) who received 2 doses and 29,901 (21%) 3 doses, totaling 239,556 doses. Eight categories were significantly increased in at least one analysis (Table). On review, most findings were previously known, preceded vaccination, or were better explained by other medical history. Some day 0 allergic reactions and syncope were potentially related to vaccination. None of the 20 deaths were considered related to 9vHPV.

Table. Elevated diagnosis categories comparing risk and self-comparison intervals.

Conclusion

This large study of individuals who received only 9vHPV vaccine did not identify any new safety events related to 9vHPV administration and provides reassuring evidence of the favorable safety profile of the 9vHPV vaccine.

Disclosures

Se Li, PhD, Merck & Co., Inc. (Employee, Shareholder) Christine Velicer, PhD, Merck & Co., Inc. (Employee, Shareholder) Patricia Saddier, MD, PhD, Merck & Co., Inc. (Employee, Shareholder) 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)
7. Two-Dose 4CMenB Vaccination in Adolescents Elicits a Bactericidal Activity against 15 Outbreak-Representative Meningococcal Strains
Authors: Biolchi Alessia , Tomei Sara , Santini Laura , Gaetana Rita La , Mori Elena , Novy Patricia , Rappuoli Rino , Bekkat-Berkani Rafik , Giuliani Marzia Monica , Pizza Mariagrazia , Sciences Biological
Published: January 2021

Background

Meningococcal outbreaks have often been associated with N. meningitidis serogroup B (MenB) in high-income countries. We examined whether antibodies elicited by the 4-component MenB vaccine (4CMenB) in adolescents could induce complement-mediated bacterial killing of a panel of 14 genetically diverse MenB strains representative of outbreaks that occurred from 2001 to 2016 (11 from the US, 2 from the UK, and 1 from France). One N. meningitidis serogroup W (MenW) hyperendemic strain (UK, 2011) was also included in the analysis.

Methods

In a previous multicenter study (NCT02212457), adolescents aged 10-18y received 2 4CMenB doses 2 months apart. We tested individual sera collected from a subgroup of 20 US participants at pre-vaccination and 1 month post-second dose in a serum bactericidal assay with human complement (hSBA) against the meningococcal strain panel. Similarly, sera collected from 23 Chilean adolescents aged 11-17y (NCT00661713) were tested in a hSBA against a subset of 4 strains (3 from the US, 1 from the UK).

Results

At baseline, the percentage of US subjects with seroprotective titers (hSBA ≥ 1:4) ranged from 5% to 35%. One month after 4CMenB series completion, 65% to 100% had seroprotective titers (hSBA ≥ 1:4) against 11 out of the 14 MenB tested strains. The seroprotection rate was 45%, 25%, and 15% against the 3 remaining MenB strains. Against MenW, the percentage of adolescents with hSBA titers ≥ 1:4 was 15% at baseline and 95% one month after series completion. No significant changes in the percentage of subjects were observed when analysing hSBA titers ≥ 1:8. Moreover, the subset analysis indicated similar results for US and Chilean subjects for 3 out of 4 strains: the percentage of US vs Chilean subjects with hSBA titers ≥ 1:4 was 100% vs 100%; 80% vs 74%; 45% vs 52%. For the 4th strain, 65% of US subjects vs 91% of Chilean subjects showed a hSBA ≥ 1:4.

Conclusion

4CMenB elicited bactericidal antibodies against a panel of 14 outbreak-representative MenB strains and 1 MenW hyperendemic strain in US adolescents. No major differences were detected in the bactericidal activity of Chilean subjects vaccinated with 4CMenB when tested against a subset of 4 MenB outbreak strains, suggesting that the immune response to 4CMenB is comparable in adolescents from different geographic areas.

Disclosures

Alessia Biolchi, n/a, GSK (Employee) Sara Tomei, n/a, GSK (Employee) Laura Santini, n/a, GSK (Employee) Rita La Gaetana, n/a, GSK Vaccines (Employee, Shareholder) Elena Mori, n/a, GSK (Employee) Patricia Novy, PhD, GSK (Employee, Shareholder) Rino Rappuoli, PhD, GSK (Employee) Rafik Bekkat-Berkani, M.D, GSK (Employee, Shareholder) Marzia Monica Giuliani, n/a, GSK (Employee, Shareholder) Mariagrazia Pizza, Biological Sciences, PhD, GSK Vaccines (Employee)
9. Influenza Vaccine Rates Amongst Patients With Limited English Proficiency In A Primary Health Care Clinic; Our 3 Years Experience
Authors: Ajayi Eloho , kpehor Atsoufui , Khanal Shristi , Munir Samavia , Estepa Adrian
Published: January 2021

Background

Influenza has been recognized to be a significant cause of morbidity and mortality. It was the cause of 10.1% of all deaths recorded on death certificates during the week ending January 20, 2018.In order to reduce the risk of influenza, Centers for Disease Control recommends that every person six months and older who have no contraindications be vaccinated with the influenza vaccine.

Limited English Proficiency (LEP) describes individuals who have limited ability to speak, read, write or understand English language. Sadly, there is an increasing body of data that suggest that patients with LEP are less likely to seek out medical attention in a timely manner, are less adherent to medically recommended preventive and therapeutic measures. The purpose of this study was to determine the rate of acceptance of the Influenza vaccine amongst patients with LEP in our resident ran out-patient clinic.

Methods

This study was retrospective, data was obtained through chart review of the electronical medical records (EMR). Patients had to be at least 18 years old and registered patients at our primary health care clinic to be enrolled in this study. Data was gathered for the 2015–2016, 2016–2017 and 2017–2018 influenza seasons. The months of October to May were designated as the Influenza season as these months have been identified as the time frame that the influenza virus has the most activity.

Results

109 of 499 the randomly selected participants were not included in the final analysis due to reasons like: no visit to the primary health care clinic during specified periods, ability to communicate in English, insufficient data in to the EMR. Data from 390 patients were analyzed. 43.3% spoke Spanish, 36.2% were Portuguese speaking and 20.5% spoke other languages. A large majority of patients across all language groups did not receive the influenza vaccine each season.

Table 1

Figure 1

Figure 2

Conclusion

Results from this study indicate that there was an alarmingly low rate of influenza vaccination among patients with LEP in our primary care clinic in during the 2015–2016, 2016–2017 and 2017–2018 influenza seasons. This highlights the need for implementing interventions aimed at both understanding why this vaccination gap exist and improving the vaccine acceptance rate amongst this venerable population.

Disclosures

All Authors: No reported disclosures
14. A Comprehensive Real-World Analysis to Compare Adjuvanted Trivalent Influenza Vaccine and Trivalent High Dose Influenza Vaccine by Age and Period of High Influenza Activity for the 2018–19 Season among U.S. Elderly
Authors: Postma Maarten , Pelton Stephen I , Divino Victoria , Mould-Quevedo Joaquin F , Shah Drishti , DeKoven Mitchell
Published: January 2021

Background

Influenza vaccine effectiveness decreases with increasing age due to the senescence of immune function and a reduced immune response to antigens. There is also considerable vaccine effectiveness heterogeneity depending on the influenza activity time period, especially in seasons where two different circulating strains predominated, such as the 2018–19 season. This research aimed to assess the effect of age and high influenza activity period (HIAP) on the relative vaccine effectiveness (rVE) of adjuvanted trivalent influenza vaccine (aTIV) vs. trivalent high-dose influenza vaccine (HD-TIV) among elderly (≥65y) recipients in the U.S.

Methods

During the 2018–19 influenza season, a retrospective cohort analysis was conducted using professional fee, prescription claims and hospital charge master data in the U.S. The first sub-analysis evaluated rVE for different age groups (65–74 years, 75–84 years, ≥85 years). The second sub-analysis evaluated rVE overall, restricting the observation period from to HAIP: Dec 2018-Mar 2019 (August 2018-July 2019 in the main analysis). Adjusted analyses were conducted through inverse probability of treatment weighting (IPTW) to control for selection bias. Poisson regression was used to estimate the adjusted pairwise rVE for influenza-related hospitalizations/emergency room (ER) visits and office visits.

Results

Following IPTW, 561,315 recipients of aTIV and 1,672,779 of TIV-HD were identified. Following IPTW adjustment and Poisson regression, aTIV was more effective in reducing influenza-related office visits compared to TIV-HD (7.0%; 95% CI: 2.6%-11.2%) in the HIAP sub-analysis. In the age sub-analysis, the rVE favoring aTIV ranged from 5.1% (95% CI: -0.17%-10.1%) for the youngest group (65–74) up to 11.4% (95% CI: 0.6%-21.1%) for the eldest group (≥85y) for influenza-related office visits. No statistically significant differences were found for aTIV compared to TIV-HD for prevention of influenza-related hospitalizations/ER visits in the sub-analyses evaluated.

Conclusion

In adjusted analyses, aTIV reduced influenza-related office visits compared to TIV-HD within the two older age groups and HIAP sub-analysis. aTIV and TIV-HD demonstrated comparable reductions in influenza-related hospitalizations/ER visits.

Disclosures

Maarten Postma, Dr., IQVIA (Consultant) Stephen I. Pelton, MD, Merck vaccine (Consultant, Grant/Research Support)Pfizer (Consultant, Grant/Research Support)Sanofi Pasteur (Consultant, Other Financial or Material Support, DSMB)Seqirus Vaccine Ltd. (Consultant) Victoria Divino, PhD, Seiqrus Vaccines Ltd. (Consultant) Joaquin F. Mould-Quevedo, PhD, Seqirus Vaccines Ltd. (Employee, Shareholder) Drishti Shah, PhD, Seqirus Vaccines Ltd. (Consultant) Mitchell DeKoven, PhD, Seqirus Vaccines Ltd. (Consultant)
15. A Novel Approach to Bacterial Vaccines: Haemophilus influenzae as a Paradigm
Authors: Stull Terrence , Whitby Paul , Morton Daniel , Mussa Huda , Mirea Lucia
Published: January 2021

Background

The H. influenzae type b vaccines target the type b capsule and therefore have no impact on the nontypable (unencapsulated) H. influenzae (NTHi). NTHi has become the most common cause of otitis media and is the most common isolate from patients with exacerbations of Chronic Obstructive Pulmonary Disease (COPD). Therefore, NTHi is an appropriate target for vaccine development.

Methods

To characterize potential vaccine targets, the core outer proteins of NTHi present in the available sequenced genomes were identified through genomic bioinformatics. The structures of the outer proteins were analyzed through comparison with the available structures of homologues characterized by X-ray crystallography. Sequenced conserved outer regions of these proteins were analyzed for their protective capacity in the infant rat model of H. influenzae infection.

Results

Nine peptides that were protective in the infant rat model were used in a novel vaccine to immunize chinchillas, the most established animal model of otitis media. Chinchillas (40 vaccinated and 41 controls) were infected with NTHi 86-028NP. The vaccinated group cleared infection more quickly than the control group as indicated by significantly decreased positive findings on video-otoscopy (p< 0.0001) and tympanometry (p=0.0002) on day 7, and presence of middle ear fluid obtained by aspiration (p=0.0001) on day 10 post infection. Similarly, in the mouse model of NTHi pulmonary clearance, the vaccinated group (n=5) reduced infection more rapidly than the control group (n= 5), p=0.008.

Conclusion

These data demonstrate the effectiveness of the Bacterial Vaccine Polypeptide methodology in development of a vaccine against NTHi with protection in relevant preclinical models of both otitis media and pulmonary clearance. The methods are applicable to other bacteria, and this approach to a Bacterial Vaccine Polypeptide against NTHi serves as a paradigm for development of similar vaccines to protect against other bacterial infections.

Disclosures

All Authors: No reported disclosures
16. A Randomized Phase 1 Study of a Novel Pneumococcal Conjugate Vaccine in Healthy Japanese Adults in the United States
Authors: Fitz-Patrick David , Young Jr. Mariano , Scott Daniel , Scully Ingrid L , Baugher Gary , Peng Yahong , Jansen Kathrin U , Gruber William C , Watson Wendy
Published: January 2021

Background

Because of the number and variability of serotypes causing pneumococcal disease among different geographic regions, age groups, and environmental backgrounds, expanding serotype coverage with pneumococcal conjugate vaccines (PCVs) is a continued unmet need.

Methods

This phase 1, randomized, double-blind study included healthy Japanese adults aged 18–49 years residing in the United States. Subjects were randomized 1:1:1 to receive a single dose of a 20-valent PCV (containing 13-valent PCV [PCV13] serotypes plus 8, 10A, 11A, 12F, 15B, 22F, 33F), a novel pneumococcal polysaccharide conjugate vaccine with extended coverage, or PCV13 (control). Safety was the primary endpoint and included reactogenicity events occurring ≤ 14 days after vaccination, adverse events (AEs) ≤ 1 month after vaccination, and serious AEs (SAEs) ≤ 6 months after vaccination. The secondary endpoint was pneumococcal serotype-specific immunogenicity as determined by opsonophagocytic activity (OPA) titers on sera collected before and 1 month after vaccination.

Results

Overall, 35 subjects received PCV20 and 35 subjects received PCV13. One subject withdrew before the 1-month follow-up. Local reactions and systemic events across groups were generally mild or moderate (Figure 1). Two vaccine-related AEs occurred (injection site erythema and swelling in the PCV20 group); no severe AEs, SAEs, or safety-related withdrawals were reported. OPA geometric mean titers increased for all 20 serotypes in the PCV20 group and all 13 serotypes in the PCV13 group 1 month after vaccination; corresponding OPA geometric mean fold rises from baseline to 1 month after vaccination are reported (Figure 2; Figure 3).

Figure 1

Figure 2

Figure 3

Conclusion

PCV20 was well tolerated and induced serotype-specific functional OPA immune responses that are anticipated to be associated with protection in Japanese adults. ClinicalTrials.gov: NCT03642847. Funding: Pfizer Inc.

Disclosures

David Fitz-Patrick, MD, Pfizer Inc (Grant/Research Support) Mariano Young Jr., MD, Pfizer Inc (Employee, Shareholder) Daniel Scott, MD, Pfizer (Employee, Shareholder) Ingrid L. Scully, PhD, Pfizer Inc (Employee, Shareholder) Gary Baugher, PharmD, Pfizer Inc (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Wendy Watson, MD, Pfizer (Employee, Shareholder)
17. Assessment of Recombinant Zoster Vaccine Second Dose Completion in the United States
Authors: Patterson Brandon J , Chen Chi-Chang , McGuiness Catherine B , Glasser Lisa I , Sun Kainan , Buck Philip O
Published: January 2021

Background

Recombinant Zoster Vaccine (RZV) was licensed in the United States (US) in October 2017 for the prevention of herpes zoster in adults ≥ 50 years of age (YOA). The vaccine is administered in a two-dose sequence with a 2- to 6-month interval; however, the Center for Disease Control & Prevention has advised against restarting a series after the prescribed window. This study describes an assessment of 2nd dose completion and compliance of RZV in the US.

Methods

Primary analysis was conducted on a cohort ≥ 50 YOA who received an initial RZV dose between October 2017 and September 2018 as indicated in the IQVIA longitudinal prescription claims or medical claims databases. Subjects were required to have ≥ 1 year of observable time post initial dose. A sensitivity analysis was conducted using all eligible subjects regardless of observable time post initial dose. Endpoints of analyses were monthly and cumulative 2nd dose label-compliant proportions at 6 months and completers by 12-month intervals and time to completion from initial RZV vaccine administration with stratifications by age, sex, claim source and payer type.

Results

The primary sample included 1,225,088 subjects, while the sensitivity analysis included 7,097,441 (Table 1). Overall, 2nd RZV dose completion was 70.4% within 6 months and 81.8% within 12 months. Minimal variation for 12-month completion was demonstrated across age (77.2–84.5%), sex (81.7–81.9%), and Commercial vs. Medicare (80.9–83.0%). However, larger variations were seen across claim sources and other payer type, with medical claims (64.9%), Medicaid patients (72.8%) and Cash patients (74.7%) having lower rates at 12 months (Table 2). Overall, the average time to completion was around 4 months regardless of stratification except by claims source, with medical claims taking 5 months on average to complete. The sensitivity analysis of the variable follow-up cohort demonstrated findings consistent with that of the primary sample.

Conclusion

Assessment of RZV suggests high levels of completion across age, sex, payer type and claim sources. More effort is needed to understand barriers to completion rates in Medicaid patients and settings where vaccination claims are processed outside of the vaccine recipient’s pharmacy benefit.

Disclosures

Brandon J. Patterson, PharmD, PhD, GSK (Employee, Shareholder) Chi-Chang Chen, PhD, MSPharm, GSK (Research Grant or Support) Catherine B. McGuiness, MA, MS, GSK (Research Grant or Support)Pfizer (Shareholder) Lisa I. Glasser, MD, GSK (Employee, Shareholder) Kainan Sun, MS, PhD, GSK (Research Grant or Support) Philip O. Buck, PhD, MPH, ORCID: 0000-0002-3898-3669, GSK (Employee, Shareholder)