bluuebunny/crossref_metadata_2025 huggingface dataset:
158. Invasive Group B Streptococcal Diseases in Adults: A Retrospective Study in Thailand (2013–2017)
Authors: Angkasekwinai Nasikarn , Pirogard Nantaporn , Phoompoung Pakpoom , Leelaporn Amornrut
Published: October 2019

Background

Group B Streptococcus (GBS) has been increasingly associated with invasive diseases in nonpregnant adults. This study aims to describe the epidemiology of invasive GBS (iGBS) diseases in adult patients.

Methods

A retrospective cohort study was conducted at Siriraj Hospital between January 1, 2013 and December 31, 2017. We included adult patients with a positive culture of GBS isolated from sterile sites.

Results

Among 224 patients recruited to the study, 170 patients (75.9%) had bacteremia. The median age of all patients was 63 years (IQR 53–73 years) and 52.7% were female. Approximately 80% of all patients had comorbid diseases. Diabetes mellitus (38.8%), cancer (18.8%) and heart disease (12.5%) were the three most common comorbidities. Skin and soft-tissue infection (30.8%), septic arthritis (21.4%), primary bacteremia (21%), and meningitis (7.1%) were the four most common presenting syndrome of iGBS diseases. Overall mortality within 30 days of infection was 12%. Non-survived patients were older, had chronic kidney disease, bacteremia, pneumonia and had at least one comorbidity than survived patients. However, only pneumonia was found independently associated with the 30-day overall mortality, with adjusted odd ratio (aOR) of 24.96 (95% confidence interval [CI]: 5.95–104.75). Antimicrobial susceptibility testing of 69 isolates demonstrated that 7 (10%) and 9 (13%) were resistant to erythromycin and clindamycin, respectively. All isolates remain susceptible to penicillin.

Conclusion

Invasive GBS is an emerging disease in non-pregnant adults particularly in elderly and diabetes mellitus patients. Two-thirds of iGBS patients have concomittant bacteremia. Even though the overall mortality was 12% but a significant morbidity was observed.

Disclosures

All authors: No reported disclosures.
2657. Clinical Prediction Tool for Multidrug-Resistant Organisms Among Deceased Donors at the Time of Donor Evaluation
Authors: Anesi Judith A , Anesi Judith A , Blumberg Emily , Han Jennifer , Lee Dong Heun , Clauss Heather , Climaco Antonette , Hasz Richard , Molnar Esther , Alimenti Darcy , West Sharon , Bilker Warren , Tolomeo Pam C , Lautenbach Ebbing
Published: October 2019

Background

Transplant guidelines recommend exercising caution when considering organs that may be infected or colonized with multidrug-resistant organisms (MDROs) and treating the organ recipient with perioperative antibiotics active against the donor MDRO. Unfortunately, donor MDROs are often identified only after transplantation. We developed a clinical prediction tool to stratify donors’ MDRO risk at the time of donor evaluation.

Methods

A retrospective cohort study was conducted at four transplant centers in Philadelphia between January1, 2015 and June 30, 2016. All deceased organ donors who donated ≥1 organ to one of the centers were included. Multivariate logistic regression was used to determine predictors of donor MDROs, including methicillin-resistant S. aureus (MRSA), vancomycin-resistant enterococci, extended-spectrum cephalosporin-resistant (ESC-R) or carbapenem-resistant Enterobacteriaceae, multidrug-resistant (MDR) P. aeruginosa, or MDR Acinetobacter species. Manual forward selection was utilized to maximize the area under the receiver operating characteristic curve (AUC). A scoring system was developed based on the odds ratios for each covariate. Internal validity was assessed using the Hosmer–Lemeshow statistic, specificity, and negative predictive value (NPV).

Results

Of 440 total donors, 62 (14%) grew MDROs on culture. The majority were MRSA (40) or ESC-R Enterobacteriaceae (20). The most parsimonious model that predicted donor MDROs included: a terminal hospitalization ≥ 7 days (1 point), ≥ 2 antibiotics administered during the terminal hospitalization (1 point), receipt of extracorporeal membrane oxygenation (ECMO) (1 point), and presence of opacities on donor chest imaging concerning for lower respiratory tract infection (2 points). With this scoring system, the maximum attainable score is 5; any donor with a score of ≥ 2 points would be considered high risk for an MDRO, with an AUC of 0.71, specificity of 99%, and NPV of 86%. The Hosmer–Lemeshow P = 0.68.

Conclusion

The risk of an MDRO among deceased organ donors can be predicted using the above scoring system. This tool will inform decisions about organ utilization and perioperative prophylaxis for solid-organ transplant recipients.

Disclosures

All authors: No reported disclosures.
2667. Does Ceftazidime–Avibactam (CAZ-AVI) Improve Short- and Long-Term Outcomes Among Solid-Organ Transplant (SOT) Recipients with Carbapenem-Resistant Enterobacteriaceae (CRE) Infections?
Authors: Sun Jonathan , Clancy Cornelius J , Shields Ryan K , Nguyen Minh-Hong
Published: October 2019

Background

SOT recipients are an ideal population in which to study the impact of new antibiotics, since they are particularly dependent upon drug activity to clear infections. In 3/15, FDA approved CAZ-AVI, the first new anti-CRE agent to arrive in the clinic. Our objective was to determine whether CAZ-AVI improves short- and long-term outcomes of CRE-infected SOT recipients.

Methods

We performed a retrospective study of SOT recipients infected with CRE since 2012, who were treated with CAZ-AVI or salvage agents for ≥ 3 days.

Results

35 CRE-infected SOT recipients (14 liver, 11 lung, 6 kidney, 3 intestine, 1 heart) with bacteremia (20), pneumonia (11), intra-abdominal abscess (3) and soft-tissue infection/osteomyelitis (1) were enrolled. 16 and 19 patients (pts) were treated with CAZ-AVI and salvage agents, respectively. Types of infection or SOT, APACHE II and McCabe scores did not differ significantly between patients treated with CAZ-AVI or salvage agents. 30- and 90-d mortality rates were significantly lower among SOT recipients treated with CAZ-AVI (0% and 6%, respectively) compared with salvage agents (26% and 37%; P = 0.049 and 0.047). Among patients who survived 90 days, recurrent CRE infections were diagnosed in 53% and 17% of those treated with CAZ-AVI and a salvage regimen, respectively (P = 0.10). Median time from end of therapy for the 1st CRE infection to recurrent infection was 116 days (max 1,242) and 361 days (max 799) for CAZ-AVI and salvage regimens, respectively. Survival and recurrence-free survival were greater for treatment with CAZ-AVI and salvage agents, respectively, as measured by Kaplan–Meier (Figures). CAZ-AVI resistance developed in 37% (n = 3) of patients with recurrent infections. Recurrent isolates were genetically indistinguishable from parent isolates by core genome SNP phylogeny (< 15 SNP).

Conclusion

CAZ-AVI significantly reduced short-term mortality among SOT recipients with CRE infections compared with salvage regimens, but was limited by recurrent infections and emergence of resistance. The same strains caused recurrent and initial infections, suggesting that CAZ-AVI did not eliminate CRE from GI sites that serve as sources of recurrence. Optimizing outcomes in SOT recipients with CRE infections will require new agents like CAZ-AVI, and strategies to eliminate long-term colonization.

Disclosures

All authors: No reported disclosures.
2679. Factors Associated with Multidrug-resistant Gram-Negative Bacteremia in Acute Leukemia Patients with Neutropenic Fever, a Retrospective Study
Authors: Chaiittiporn Dudrudee , Prasongdee Klaorat , Kongkiatkamon Sunisa , Jutivorakool Kamonwan , Vanichanan Jakapat
Published: October 2019

Background

Gram--negative bacteremia in acute leukemia patients with neutropenia is associated with high morbidity and mortality rate. Appropriate antibiotic for empirical treatment is crucial; however, antibiotic selection is challenging especially in setting with high prevalence of infections with multidrug-resistant (MDR) organisms. Data on associated factors of MDR Gram-negative bacteremia in this population is limited.

Methods

A retrospective study was conducted in King Chulalongkorn Hospital, Bangkok, Thailand. Medical records of patients aged ≥15 years with acute leukemia who were hospitalized in our institute and had neutropenic fever between 1 January 2001 and 31 December 2016 were reviewed. Demographic data, causative organisms, treatment and outcomes were documented. Episodes of MDR Gram-negative bacteremia were compared with non-MDR group. Associated risk factor was assessed by multivariate logistic regression

Results

From total 405 admission records of 227 acute leukemia patients, 587 episodes of neutropenic fever occurred with 131 episodes of Gram-negative bacteremia. Majority (81.68%) were bacteremia without source of infection. Most common causative pathogens were E. coli, P. aeruginosa and K. pneumoniae, respectively. Sixty episodes of Gram-negative bacteremia (53.57%) were caused by MDR pathogen. Associated factor for MDR Gram-negative bacteremia was prior colonization or infection with MDR Gram-negative bacteria within 3 months (P = 0.049). Subgroup analysis in patients with non-lactose fermenter bacteremia showed higher rate of intensive care unit (ICU) admission and in-hospital death in MDR group (P = 0.03 and P = 0.004).

Conclusion

Prior colonization or infection by MDR Gram-negative bacteria within 3 months was associated with MDR Gram-negative bacteremia in acute leukemia patients with neutropenic fever. Thoroughly review of previous culture data and active screening for colonization may increase chance of appropriate empirical antibiotics.

Disclosures

All authors: No reported disclosures.
2696. Breakthrough Toxoplasmosis While on Atovaquone Prophylaxis Following Allogeneic Hematologic Stem Cell Transplantation
Authors: Chueng Teresa A , Raja Mohammed A , Morris Michele I , Komanduri Krishna V , Camargo Jose F
Published: October 2019

Background

The opportunistic parasite Toxoplasma causes life-threatening complications in immunocompromised hosts such as hematopoietic cell transplantation (HCT) recipients. Trimethoprim-sulfamethoxazole (TMP-SMX) is the agent of choice in preventing Pneumocystis jirovecii pneumonia and Toxoplasma, but bone marrow suppression often precludes its use. Broad-spectrum atovaquone also targets protozoan tachyzoite and cyst forms, but few studies examine its efficacy in prophylaxis among this vulnerable population. We present two HCT patients experiencing breakthrough toxoplasmosis despite compliance with atovaquone prophylaxis.

Methods

Review of literature and electronic medical records.

Results

Case 1. A 68-year-oldToxoplasma seropositive woman with myelodysplastic syndrome underwent Flu-Mel-ATG-matched unrelated donor HCT. On day +68 post HCT, she presented with encephalopathy. MRI brain revealed solid and ring-enhancing lesions correlating with positive CSF T. gondii PCR. Serum DNA PCR was negative. She received 12 weeks of sulfadiazine, pyrimethamine, and leucovorin with clinical and radiological improvement. Atovaquone prophylaxis was restarted given pancytopenia intolerance of TMP-SMX. Despite compliance, she experienced recurrent central nervous system toxoplasmosis. Her demise followed an unrelated ischemic cerebrovascular accident. Case 2. A 53-year-old Toxoplasma seropositive woman with CMV viremia and severe aplastic anemia limiting TMP-SMX use presented with pancytopenia on day +46 after HCT. Diagnosed with graft failure, routine screening revealed positive Toxoplasma PCR while on atovaquone prophylaxis. Toxoplasma PCR became negative after preemptive therapy. She underwent a second Flu-Cy-ATG-TBI-matched related donor HCT. 2 months later, medication noncompliance led to readmission with CMV viremia and culture-negative sepsis. Blood Toxoplasma PCR was positive at the time of death.

Conclusion

Toxoplasmosis prophylaxis failure can occur in allogeneic HCT recipients receiving atovaquone. When possible, TMP-SMX should remain first-line agent for this indication. In those unable to tolerate TMP-SMX, close clinical and Toxoplasma PCR monitoring may help identify reactivation and facilitate early initiation of therapy.

Disclosures

All authors: No reported disclosures.
2711. Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease in Older Adults
Authors: Lewis Ned , Hsiao Amber , Hansen John , Yee Arnold , Chao Charlie , Suaya Jose A , Alexander-Parrish Ronika , Isturiz Raul E , McLaughlin John M , Gessner Bradford D , Klein Nicola
Published: October 2019

Background

Routine use of 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for infants since early 2010 and for adults ≥65 years since 2014 when KPNC began routine use of PCV13 in adults. PCV13 vaccine effectiveness (VE) against vaccine-type invasive pneumococcal disease (IPD) has been demonstrated; however, recent surveillance data have been interpreted as showing limited population-level impact of PCV13 on serotype 3 IPD. We estimated PCV13 VE against IPD due to vaccine serotypes at Kaiser Permanente Northern California (KPNC).

Methods

The study period spanned September 2014 through September 2018. The cohort included KPNC members who were aged ≥65 years with no record of pneumococcal polysaccharide vaccine (PPV23) receipt before age 65 years. We compared IPD cases with KPNC members who were the same age on the date of the positive pneumococcal culture using conditional logistic regression, conditioned on age and date, and controlled for sex, race, KPNC service area and membership history, prior season influenza vaccine receipt, PPV23 receipt after age 65 years, risk factors for IPD, and healthcare utilization.

Results

From September 2014 to September 2018, PCV13 vaccine coverage among persons ≥65 years old increased from < 1% to 77%. During the same period, there was a total of 245 IPD cases. For a variety of reasons, we did not have serotype results for 57 (23%) IPD cases, which were excluded from the analysis. There were 61 (25%) PCV13-type IPD cases included in the analysis, of which 33 (14%) were serotype 3. PCV13 VE against PCV13-type serotypes was 68.0% (95% CI: 37.7%, 83.6%; P-value < 0.01), and 53.4% (95% CI: −10.0%, 80.3%; P = 0.08) against serotype 3.

Conclusion

During the first 4 years of PCV13 vaccination implementation in adults ≥65 years of age at KPNC, PCV13 provided significant protection against PCV13-type IPD. Further surveillance will allow for more precise estimation of PCV13 VE on overall and serotype 3 IPD over time.

Disclosures

All authors: No reported disclosures.
2718. Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine in US Adults Hospitalized with Pneumonia, 2014–2017
Authors: Lessa Fernanda C , Spiller Michael , Wu Xiyuan , Wang Rongrong , Chillarige Yoganand , Wernecke Michael , MaCurdy Thomas E , Kelman Jeffrey A , Shang Nong , Pilishvili Tamara
Published: October 2019

Background

Efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) against pneumococcal pneumonia in adults aged >65 years was shown in a 2014 clinical trial. However, its benefits in countries with a mature PCV infant program remain unclear. In August 2014, PCV13 was recommended for all US adults aged >65 years. We evaluated the direct effect of this recommendation on pneumonia hospitalizations among the elderly.

Methods

We analyzed claims data from US Medicare beneficiaries aged >65 years enrolled in part A/B during September 1, 2014 through December 31, 2017. Participants were followed until they died, left part A/B, or developed a study outcome: community-acquired pneumonia (CAP), non-healthcare-associated CAP (non-HA CAP) or lobar pneumonia (LP). We identified outcomes using inpatient diagnosis codes, and vaccination status using procedure codes. We used discrete-time survival models, stratified by influenza season (October–April) and influenza vaccination status, to estimate incidence rate ratios (IRR) by pneumococcal vaccination status (PCV13-only vs. no pneumococcal vaccination). We adjusted for demographic factors, healthcare utilization, month/year of hospital discharge, and underlying conditions. We derived vaccine effectiveness (VE) and number of hospitalizations averted by PCV13 from the IRRs.

Results

Of 26.6 million beneficiaries in September 2014, 43.4% were male, 54.2% were aged 65–74 years, and 28.9% had a Charlson comorbidity score >3. PCV13 coverage increased from 0.8% in September 2014 to 41.5% in December 2017. Annual incidence of CAP, non-HA CAP, and LP are shown in the figure. PCV13-vaccinated persons were more likely to be older, sicker, and have received flu vaccine than unvaccinated persons. VE estimates for CAP, non-HA CAP, and LP ranged from 6.0–11.4%, 5.0–11.0%, and 1.3–11.0%, respectively. From September 2014 to December 2017, an estimated 28,600 (95% CI: 21,000–36,000) CAP, 18,700 (12,000–25,800) non-HA CAP and 1,100 (190–1,900) LP hospitalizations were averted.

Conclusion

Within 40 months after implementation of the adult PCV13 program, 2.0% (28,600) of US CAP hospitalizations were averted. Despite PCV13 effectiveness against adult CAP, only a small fraction of CAP hospitalizations was prevented.

Disclosures

All authors: No reported disclosures.
2730. Estimating Deaths Attributable to Influenza Mortality Using Traditional and Novel Forecasting Methods
Authors: McConeghy Kevin , Zullo Andrew R , Van Aalst Robertus , Bosco Elliott , Gravenstein Stefan
Published: October 2019

Background

Seasonally-adjusted linear models (‘Serfling’ models) serve as an important surveillance measure to estimate influenza (flu) attributable deaths for resource allocation to public health programs (e.g., vaccination campaigns). We compared performance of traditional time-series and viral activity-based models to a novel open-source R-package ‘Prophet’ for estimating the number of deaths attributable to influenza per season.

Methods

We evaluated deaths from the 122-Cities Mortality Reporting System which reports the total number of death certificates where pneumonia or flu was listed as a contributing cause of death. Models were fitted to 2010–2015 influenza seasons. The first Serfling model (M1) used baseline periods of low-endemicity (summer months) to estimate attributable deaths during a flu season (OCT-MAY), the second Serfling model (M2) incorporated both baseline and virology data (count laboratory proven flu cases in a given period). The Prophet model (M3) uses generalized additive models incorporating annual, seasonal terms and viral activity data. The difference between observed deaths, and those predicted by each model in the absence of flu were ‘attributable death.” Epidemic weeks exceeded the 95% upper prediction interval. Model performance was assessed by Root Mean Square Error (RMSE).

Results

From 2010 to 2015, the average deaths due to pneumonia and influenza per season numbered 824 per week (total 198,692). Compared with the traditional Serfling model (M1), the Prophet model estimated 52% more influenza-attributable deaths (13,443 vs. 8,800) and more epidemic weeks (25 vs. 10) with lower RMSE (75.9 vs. 95.3 [lower is better]). Compared with the viral activity-based model (M2), the Prophet model estimated 6% fewer attributable deaths (13,443 vs. 14,326), with more epidemic weeks (25 vs. 19) and lower RMSE (RMSE 75.9 vs. 92.6).

Conclusion

Generalized additive models, implemented through the R-package Prophet, are superior in terms of reducing model prediction error for influenza mortality vs. traditional models. Based on superior model performance, the attributable mortality estimated by these novel models may be preferred over traditional regression models. This study was funded by Sanofi Pasteur.

Disclosures

All authors: No reported disclosures.
166. Comparison of Oral Fluoroquinolones to Alternative Oral Agents for Definitive Step-Down Therapy in Gram-Negative Bloodstream Infections
Authors: Cho Christian Y , Dillon Caroline , Carr Dustin R , Walsh Thomas L , Moffa Matthew , Bremmer Derek N
Published: October 2019

Background

During the management of Gram-negative bloodstream infections (GN BSIs), definitive oral step-down therapy is often utilized. Fluoroquinolones (FQs) are commonly utilized due to excellent bioavailability; however, comparative evidence to oral trimethoprim/sulfamethoxazole (TMP/SMX) or β-lactams (BLs) are limited.

Methods

This multicenter, retrospective cohort included patients ≥18 years of age who had a GN BSI and received oral FQ, BL, or TMP/SMX as definitive oral step-down therapy for >33% of their total treatment duration. Patients were excluded if received ˂7 days or >17 days of total therapy, or had polymicrobial bacteremia. The primary outcome was treatment failure within 90 days. Treatment failure was a composite endpoint including both all-cause mortality and recurrence of infection. Secondary outcomes included all-cause and infection-related readmissions at 30 days.

Results

A total of 220 patients were included (FQ n = 106, BL n = 96, SMX/TMP n = 18). Patients were elderly (median age 70 years; IQR 59–79) and had a median Pitt bacteremia score of 1 (IQR 0–2). The most common pathogens were E. coli (58.2%) and K. pneumoniae (17.3%) and the primary source of infection was urinary (70%). Majority of BL use consisted of cephalexin (44.7%) and cefuroxime (21.3%) while FQ use was mostly ciprofloxacin (69.8%). Infectious diseases consultations were associated with 52.8%, 39.6%, and 72.2% of the prescribed FQ, BL, and SMX/TMP, respectively. Overall median intravenous, oral, and total effective antibiotic durations were 3.9, 9, and 13 days, respectively, and were similar between each group. Ninety day treatment failure rates were 9.5% in the FQ group vs. 14.6% in the BL group (P = 0.27) and 0% in the TMP/SMX group (P = 0.35). All-cause and infection-related readmissions were similar between FQ, BL, and TMP/SMX: (25.5%, 27.1%, 16.7%; P = 0.73) and (4.7%, 5.2%, 5.6%; P = 1.0), respectively.

Conclusion

We identified similar treatment failure rates between oral FQs, BLs, and TMP/SMX. Oral step-down therapy with BLs may be a promising FQ-sparing option for the definitive treatment of GN BSIs. Limitations to TMP/SMX efficacy should be interpreted with caution due to the small sample size. Further investigations into optimal and tolerable oral dosing of such agents are needed.

Disclosures

All authors: No reported disclosures.
2738. Influenza Vaccination During Pregnancy Among Mothers of Infants with Acute Respiratory Illness, United States, 2016–2018
Authors: Ogokeh Constance E , Patel Manish , Lively Joana Y , Staat Mary A , Weinberg Geoffrey A , Boom Julie A , Englund Janet A , Williams John V , Halasa Natasha B , Selvarangan Rangaraj , Harrison Christopher J , Klein Eileen J , Schlaudecker Elizabeth P , Michaels Marian G , Sahni Leila C , Szilagyi Peter G , Stewart Laura S , Rha Brian , Beacham Lauren , Bardenheier Barbara , Payne Daniel C , Fry Alicia M , Campbell Angela P
Published: October 2019

Background

Influenza vaccination has been shown to reduce influenza risk in pregnant women and their infants who are not yet age-eligible for vaccine. Ascertainment of vaccination history is important for vaccine safety and effectiveness evaluations. Our goals were to (a) determine coverage, location, and timing of maternal influenza vaccination and (b) compare a subset of self-reported influenza vaccinations with documented vaccine records.

Methods

We enrolled children < 18 years. with acute respiratory illness in 7 pediatric hospitals and emergency departments in the New Vaccine Surveillance Network from December 1, 2016 to October 31, 2018. We interviewed all mothers of enrolled infants < 1 year, and obtained mother’s influenza vaccine information while pregnant. As an option, sites obtained maternal influenza vaccine records from reported sources (e.g., registries, provider records, pharmacies).

Results

Among 5,458 mothers, 2,944 (54%) self-reported receiving influenza vaccine during pregnancy (57% in 2016–2017; 51% in 2017–2018), varying from 49% to 74% by site. Among self-reported vaccinees, 17%, 36%, and 47% received vaccine during their first, second, and third trimester, respectively. Most women (76%) were vaccinated at their OB/GYN or midwife office, 7% at their primary care provider, 7% at their workplace, and 5% at a retail pharmacy. Among 1,338 infants < 6 months. during early influenza season (i.e., born from June to August) and thus ineligible for vaccination, only 46% of mothers reported receiving vaccine during pregnancy (42% reported not receiving it, 12% were unsure). Of 2,242 women for whom vaccine verification was attempted, 1,491 (67%) self-reported receiving influenza vaccine during pregnancy; of those, documentation of vaccine receipt was found for 901 (60%).

Conclusion

Influenza vaccination coverage among pregnant women was suboptimal, potentially increasing the risk of influenza in unvaccinated pregnant women. Infants born to unvaccinated women, particularly those born from June to August, may also be at higher risk since they are not age-eligible to receive vaccine before influenza season. The optimal approach to ascertainment of maternal vaccination history with accuracy and completeness merits further investigation.

Disclosures

All authors: No reported disclosures.
2744. A Phase I Randomized, Observer-Blind, Controlled, Dose Escalation Trial of the Safety and Tolerability of a Single Intramuscular Dose of a PAL Adjuvant (Laboratory Code, FB-631) Co-administered with Seasonal TIV (2013–2014) to Healthy Adults ≥18–50 Years of Age
Authors: Langley Joanne Marie , Pastural Elodie , Halperin Scott , Halperin Scott , McNeil Shelly , ElSherif May , MacKinnon-Cameron Donna , Ye Lingyun , Lapointe Rejean , McElhaney Janet , Martin Luis , Bolduc Marilène , Laliberté-Gagné Marie-Ève , LeClerc Denis , Savard Pierre
Published: October 2019

Background

Inactivated influenza vaccines (IV) efficacy is variable and sometimes poor. In this phase 1 trial the safety and immunogenicity of a novel nanoparticle adjuvant (Papaya Mosaic Virus (PapMV or PAL) at different dose levels combined with inactivated trivalent IV (TIV; FLUVIRAL® 2013–2014, GSK, Kirkland PQ) was assessed. Nonpathogenic in mammals, PAL is recognized as a pathogen-associated molecular pattern (PAMP) which stimulates innate, cell-mediated immunity (CMI) and adaptive immunity in naïve mice through activation of toll like receptor 7 and 8.

Methods

Healthy persons 18–50 years of age were randomized to one of 6 study groups: 30 µg, 60 µg, 120 µg or 240 µg of PAL with 0.25 mL TIV, 240 µg of PAL with 0.125 mL TIV, or control (0.5 mL TIV). Solicited local and general adverse events (AE) were collected Day (D)0 to 6, unsolicited AE to D28, and serious AE to D1095. Hemagglutination-inhibition assays (HI), antibody to Influenza A virus nucleoprotein (NP), and peripheral blood mononuclear cells (PBMC) for measurement of interferon-gamma (IFNg) ELISPOT (response to PepMix influenza A H2N2 Ann Arbour NP, MP1, and an influenza peptide pool), granzyme B, and IFNg:IL:10 ratio were collected on D0, 7, 28, 120, and 180.

Results

The most common solicited AEs were transient mild-to-moderate local pain (62.5%–87.5% of participants/group), drowsiness (≤37.5% of participants/group) and generalized muscle aches (12.5–50% of participants/group). There was one unrelated SAE. All participants had HI and anti-NP titers at baseline. HI GMTs increased at D28 post vaccine in most groups (Figure 1) and waned over time. HI fold Ab (Far) responses to TIV strains were poor in all groups (≤37.5% of participants/group had 4-Far to any strain). CMI results were consistent with humoral responses.

Conclusion

The PAL adjuvant in doses of 30 to 240µg combined with reduced TIV dosages was safe with no signals up to 3 years after vaccine. Reduced doses of TIV co-presented with 240 µg PAL had similar HI GMTs as TIV. The CMI results suggest that the assessment of PAL efficacy on TIV immunization would have to be conducted in an influenza naïve population.

Disclosures

Scott Halperin, MD, GlaxoSmithKline: Ad hoc advisory boards, Other Financial or Material Support, Research Grant; Janssen Pharm: Research Grant; sanofi pasteur: Ad hoc advisory boards, Other Financial or Material Support, Research Grant.
2750. Sequential Influenza A H1N1 and Influenza A H3N2 Challenge Infections in Healthy Volunteers
Authors: Han Alison , Giurgea Luca , Cervantes-Medina Adriana , Edwards Kristina , Rosas Luz Angela , Czajkowski Lindsay , Baus Holly Ann , Athota Rani , Reed Susan , Taubenberger Jeffery , Memoli Matthew
Published: October 2019

Background

Seasonal influenza causes significant annual morbidity and mortality. The effects of yearly exposures on immunity are not clear and recent observations have demonstrated that long lasting protection against a matched strain may not naturally occur. The 2018–2019 influenza season consisted of an initial peak of H1N1 infections followed by a wave of H3N2 infections. These consecutive waves raise questions about how influenza immunity is affected by sequential exposure to different influenza strains. Challenge studies provide a unique opportunity to study this phenomenon. Here we describe a subset of participants who were sequentially infected in two separate challenge studies with wild-type H1N1 and H3N2 viruses.

Methods

Healthy volunteers completed two sequential influenza challenge studies at the NIH Clinical Center. Participants were inoculated with reverse genetics, cell-based, GMP wild-type influenza viruses, A(H1N1)pdm09 and A(H3N2) strains. Participants remained isolated in the hospital for a minimum of 9 days and were monitored daily for viral shedding and clinical symptoms. After discharge, participants were followed for 2 months.

Results

Between 2014 and 2017, 14 healthy volunteers were exposed to Influenza A(H1N1) and Influenza A(H3N2). Time between infections ranged from 2 months to 2 years. Thirteen (93%) participants developed confirmed influenza infection after H1N1 challenge and 9 (64%) after H3N2 challenge. Eight (57%) participants developed confirmed infections after both exposures. Variable degrees of symptoms, shedding, and disease severity were observed. Systemic antibody responses to the HA and NA of both H1N1 and H3N2 varied over time during these sequential infections.

Conclusion

More than half of all participants who completed 2 sequential H1N1 and H3N2 challenge studies demonstrated confirmed infection to both viruses. These sequential infections had varying effects on the disease experienced and the immunity that developed after infection. These observations are important in understanding the impact of sequential exposures on influenza immunity.

Disclosures

All authors: No reported disclosures.
2755. Phase 1/2, First-in-Human Study of the Safety, Tolerability, and Immunogenicity of an RSV Prefusion F-Based Subunit Vaccine Candidate
Authors: Schmoele-Thoma Beate , Falsey Ann R , Walsh Edward E , Swanson Kena , Zareba Agnieszka , Cooper David , Gruber William C , Jansen Kathrin U , Radley David , Scott Daniel , Dormitzer Philip R
Published: October 2019

Background

The respiratory syncytial virus (RSV) fusion glycoprotein (F) is a molecule that fuses the viral and host cell membranes during virus entry as it rearranges from a meta-stable prefusion to a stable postfusion conformation. Using structure-guided design, Pfizer engineered a prefusion RSV F subunit vaccine antigen with stable and well-characterized conformational homogeneity.

Methods

We report results of a 1,182 subject, first-in-human, phase 1/2, placebo-controlled, randomized, observer-blind, dose-finding study to describe the safety, tolerability, and immunogenicity of the Pfizer RSV vaccine candidate in healthy men and non-pregnant women from 18 to 85 years of age. The study compares three dosages of the vaccine candidate, with and without aluminum hydroxide, and also compares immunization with the RSV vaccine candidate alone or concomitantly with influenza vaccine. The study is ongoing to collect antibody persistence and additional safety data.

Results

The data, which are currently available for the 18- to 49-year-old subgroup, demonstrate an excellent safety and tolerability profile. Immunization with the various formulations of the vaccine candidate elicited RSV 50% neutralization titer geometric mean fold rises (GMFRs) of 10.6–17.2 for subgroup A and 10.4–19.8 for subgroup B, measured one month after immunization, with evidence of a dose–response.

Conclusion

The 10- to 20-fold increases in neutralizing antibody titers elicited by this vaccine with a stable prefusion F antigen represent a step change relative to the historical performance of vaccine candidates, such as Wyeth’s PFP, with F antigens that were not stabilized in the prefusion conformation (Simoes et al., Vaccine 20:954–60, 2002). The data strongly support development of this vaccine candidate to prevent RSV disease in infants, by immunizing pregnant women, and to prevent RSV disease in older adults, by direct immunization.

Disclosures

All authors: No reported disclosures.
2761. Interventions to Improve Influenza Vaccination Coverage in Children with Medical Comorbidities: A Meta-Analysis
Authors: Norman Daniel , Barnes Rosanne , Danchin Margie , Seale Holly , Moore Hannah C , Blyth Christopher C
Published: October 2019

Background

Influenza vaccination is the most effective influenza prevention tool for children with medical comorbidities. Despite this, coverage remains inadequate. Numerous interventions to improve vaccination coverage have been assessed, yet there remains a paucity of data comparing the relative efficacy and effectiveness of different interventions.

Methods

We searched MEDLINE, PubMed, Scopus, Embase, CINAHL, CENTRAL, and Web of Science (1980 to March 2019) for studies evaluating interventions which sought to improve influenza vaccine coverage in children with medical comorbidities. Interventions were divided into those targeting parents, targeting vaccination providers, and targeting the hospital, clinic or ward. Screening and data extraction from publications meeting inclusion criteria was performed by two reviewers. Results were pooled and meta-analyses were performed using Mantel–Haenszel random-effects models in Review Manager 5.

Results

35 articles met inclusion criteria; 14 cross-sectional, 12 randomized trials, and 9 cohort studies, 25 articles had sufficient data for pooled analysis. Of the included interventions, 17 were based within primary care or community-based settings, 17 were based in hospitals or tertiary clinics, and 1 intervention was conducted across both primary and tertiary settings. Interventions overall increased influenza vaccination likelihood by 33% (RR = 1.33: 95% CI 1.31, 1.35). Interventions targeting providers’ influenza vaccine knowledge increased vaccine coverage (RR = 1.42: 95% CI 1.36, 1.49) greater than those targeting parental knowledge (RR = 1.23: 95% CI 1.21, 1.26). Conversely, vaccination reminders targeting parents increased vaccine coverage (RR = 1.53: 95% CI 1.49, 1.58) greater than reminders targeting providers (RR = 1.23: 95% CI 1.20, 1.27). Interventions targeting hospitals, clinics or ward processes had the weakest impact on coverage (RR = 1.15: 95% CI 1.13, 1.17).

Conclusion

Interventions targeting parents, providers, and places individually have all shown to improve influenza vaccination in children with medical comorbidities. However, specifically targeting providers’ vaccine knowledge and parental reminders appear to have the greatest impact on vaccine uptake.

Disclosures

All authors: No reported disclosures.
2763. Uptake and Safety of Measles-Mumps-Rubella (MMR) Vaccine in Adolescents and Adults in the Vaccine Safety Datalink
Authors: Hanson Kayla E , McLean Huong , Marin Mona , Panagiotakopoulos Lakshmi , Weintraub Eric , Daley Matthew F , Groom Holly , Jackson Lisa , Jacobsen Steven J , Klein Nicola , Nordin James D , Belongia Edward
Published: October 2019

Background

MMR vaccine is given routinely to young children but may be given at other ages. We described MMR use in adolescent and adult populations in the Vaccine Safety Datalink (VSD) and estimated the incidence of medically-attended outcomes after MMR to inform future studies estimating vaccine-associated risk.

Methods

The study population included adolescents (9–17 years) and adults (≥18 years) in VSD who received at least one MMR vaccine from 2010 through 2016. Outcomes were pre-specified based on previous vaccine safety studies and categorized as clinically serious (anaphylaxis, encephalitis/myelitis, GBS, meningitis, seizure) or non-serious (allergic reaction, arthropathy, fever, injection site reaction, lymphadenopathy, nonspecific reaction, parotitis, rash, syncope). Outcomes were identified by searching for ICD-9 and ICD-10 diagnosis codes in post-vaccination exposure windows. Medical records were reviewed for all serious outcomes to verify incident diagnoses. Incidence and 95% confidence intervals were calculated for validated serious and all non-serious outcomes.

Results

146,503 adolescents and adults received 162,992 MMR vaccines during the study period. The mean age at vaccination was 33.7 years, 65% were female, and 53% received at least one other vaccine simultaneously. Demographic and vaccination characteristics varied across age groups (Table 1). The analysis of post-vaccination outcomes included 162,053 MMR vaccinations. The incidence of validated serious outcomes was low, ranging from 0 to 6.8 per 100,000 vaccinations. Only one serious outcome (anaphylaxis) was noted to be vaccine-associated in the medical record. Incidence of clinically non-serious outcomes varied from 0.4 to 56.0 per 10,000 vaccinations. Injection site reactions were more common among adolescents (118.1 per 10,000 vaccinations), who also had a higher frequency of simultaneous vaccination (80%).

Conclusion

Clinically serious outcomes were rare following MMR vaccination. Rates of clinically non-serious outcomes varied but were similar to or lower than previous reports in children. This descriptive analysis did not evaluate the association between MMR and adverse events. Future analysis with an appropriate comparison group is needed for risk estimation.

Disclosures

All authors: No reported disclosures.
2769. The Clinical and Economic Impact of MMR Vaccinations to Prevent Measles Importations from US Pediatric Travelers Returning from Abroad
Authors: Hyle Emily P , Bangs Audrey C , Fiebelkorn Amy P , Walker Alison T , Gastanaduy Paul , Neilan Anne M , Rao Sowmya R , Ryan Edward T , LaRocque Regina C , Walensky Rochelle P
Published: October 2019

Background

Although pediatric travelers comprise < 10% of US international travelers, they account for almost half of all measles importations among returning travelers. For travelers 1–18 years with no other evidence of measles immunity, the Advisory Committee on Immunization Practices (ACIP) recommends 2 MMR vaccine doses before departure; 1 dose is recommended for infant travelers (6 to <12 months) and does not count toward their primary immunization series. All US travelers (6 months to < 6 years) are at risk for being undervaccinated for measles because MMR is routinely given at 1 years and 4–6 years.

Methods

We developed a decision tree model to evaluate the clinical impact and cost per case averted of pretravel health encounters (PHE) that vaccinate MMR-eligible pediatric international travelers. We compared 2 strategies for infant (6 to < 12 months) and preschool-aged (1 to <6 years) travelers: (1) no PHE: travelers departed with baseline MMR vaccination status vs. (2) PHE: MMR-eligible travelers were offered vaccination. All simulated travelers experienced a destination-specific risk of measles exposure during travel (mean, 237exposures/10M travelers; range, 19–6,750 exposures/10M travelers); if exposed to measles, travelers were at risk of illness stratified by age and MMR vaccination status (range, 0.03–0.90). Costs include direct medical costs and lost work wages for guardians. Model outcomes included measles cases, costs, and cost per case averted. We varied inputs in sensitivity analyses.

Results

Compared with no PHE, PHE averted 451 measles cases at $985,000/case averted for infant travelers and 54 measles cases at $1.5 million/case averted for preschool-aged travelers (table, bottom). PHE can be cost-saving for travelers to regions with higher risk of measles exposure and if more MMR-eligible travelers are vaccinated at PHE (Figure 1). At a risk of exposure associated with European travel, PHE had better value when a measles importation led to a higher number of contacts or more US-acquired cases per importation (Figure 2).

Conclusion

PHE for pediatric travelers (6 months to <6 years) decreased the number of imported measles cases and saved costs, especially if targeted to travelers with higher-risk destinations, if more MMR-eligible travelers are vaccinated at PHE, or if outbreaks are larger.

Disclosures

All authors: No reported disclosures.
2776. Post-marketing Safety Surveillance for the Adjuvanted Recombinant Zoster Vaccine: Review of Spontaneous Reports Since Introduction
Authors: Tavares-Da-Silva Fernanda , Miranda Co Maribel , Dessart Cristophe , Hervé Caroline , López-Fauqued Marta , Mahaux Olivia , Van Holle Lionel , Stegmann Jens-Ulrich
Published: October 2019

Background

The adjuvanted recombinant zoster vaccine (RZV, GSK), indicated for the prevention of herpes zoster (HZ) in adults ≥ 50 years of age, received its first marketing authorization in October 2017. We reviewed the post-marketing spontaneous adverse event (AE) reports submitted to GSK’s worldwide safety database since RZV introduction.

Methods

Descriptive analyses were conducted on all spontaneous reports involving RZV from October 13, 2017 to February 10, 2019. Observed-to-expected analyses were performed for the outcomes of interest: all-cause mortality and the 2 most commonly reported potential immune-mediated diseases, Guillain–Barré syndrome (GBS) and Bell’s palsy. Data mining was done to detect quantitative signals by identifying RZV-AE pairings with disproportionate reporting or evidence of an unexpected time-to-onset distribution.

Results

Most of the15,638 spontaneous reports received were medically verified (75.2%), originated from the United States (81.7%) and were non-serious (95.3%). Reports were mainly from individuals 50–69 years old (62.1%) and females (66.7%), when documented (Figure 1). Of all reports, 12,059 (77.1%) described signs/symptoms and 3,579 (22.9%) described vaccination errors, majority of which were without associated signs/symptoms (2,961; 82.7%). Overall, the most commonly reported signs/symptoms were consistent with vaccine reactogenicity (such as injection-site reactions, pyrexia, pain, chills, headache, fatigue), which were previously reported after RZV (Table 1). The observed reporting rates of outcomes of interest likely represent temporary associated events that are occurring as background incidence in the general population. No unexpected reporting patterns were detected overall. The proportion of RZV vaccination errors over time, by country, is shown in Figure 2. Overall, most reports described errors in vaccine preparation and reconstitution (29.7%) (Table 2).

Conclusion

Overall, the safety profile of RZV, following the first year of post-marketing use, is reassuring and consistent with that observed in clinical trials. Ongoing surveillance will continue to monitor RZV safety, as it is an early stage in the implementation, when real-life data are limited.

Funding: GlaxoSmithKline Biologicals SA.

Disclosures

All authors: No reported disclosures.
2785. Respiratory Viral Panel Testing in Intensive Care Units: Effects on Outcomes
Authors: Harris Gavin H , Hughes Kailey L , Middleton Donald , Zimmerman Richard , Silveira Fernanda P
Published: October 2019

Background

Acute respiratory viral illnesses cause significant morbidity and mortality leading to high healthcare costs. Delayed viral pathogen diagnosis likely contributes to increases in morbidity and mortality. We aimed to analyze: (1) the use of respiratory viral panel (RVP) testing in adults hospitalized to intensive care units (ICUs) with acute respiratory illness (ARI) during flu season; and (2) if RVP testing is associated with improved outcomes.

Methods

Data from adults hospitalized to the ICU with ARI during the 2015–2016, 2016–2017, and 2017–2018 influenza seasons at 3 hospitals participating in the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) study was analyzed. Details of disease severity, underlying health status, and vaccination status were obtained through enrollment interviews and medical records. Clinical RVP results were recorded. Research swabs for influenza (CDC PCR) were performed in all patients who did not have a clinical sample. Multivariate regression was used to estimate the associations between RVP and in-hospital complications.

Results

397 patients were enrolled; 263 (66%) had a clinical RVP done. 25% of patients with ≥ 1 CDC-defined high-risk condition for influenza complications did not have an RVP. 36 (9%) of patients had a positive RVP for flu (1 H1N1, 28 H3, 1 A no subtype, and 6 B). Mean time from onset of symptoms to RVP was 2.25 ± 2.24 days and mean time from ICU admission to RVP was 0.85 ± 1.27 days. 11 (8%) of patients who had only a research swab were positive for flu (1 A no subtype, others H3). 4 (36%) of these patients received oseltamivir. Use of antivirals was significantly more common in patients who had RVPs (68 vs 1%, p

Conclusion

One-third of patients admitted to the ICU with ARI during the flu season did not have an RVP, including 25% of patients with ≥ 1 high-risk condition for influenza complications. Influenza was present in 8% of patients who did not undergo clinical testing and 64% of these patients did not receive antivirals. There is room for improvement in ordering of RVPs in ICUs.

Disclosures

All authors: No reported disclosures.
490. High Prevalence of Rectal Carriage of blaKPC –Mediated Carbapenem-Resistant Enterobacteriaceae Among Community Food Handlers in Kuwait
Authors: Al-Sweih Noura , Moghnai Ola , Rotimi Vincent O
Published: October 2019

Background

Carbapenemases are diverse enzymes which inactivate the carbapenems. KPC-producing carbapenemase-producing Enterobacteriaceae have disseminated to many regions in the world, however, anecdotal reports of KPC-producing CPE in some GCC countries excluding Kuwait. In this study we report the first emergence of the KPC producing CPE isolated from healthy food handlers in our community.

Methods

Rectal swabs were collected from 405 food handlers. Isolates were identified by VITEK 2 and their susceptibility to 21 antibiotics performed by MIC determination using Etest. Genes encoding carbapenemase production were characterized by PCR and clonality of isolates was determined by MLST.

Results

A total of 36 CPE were isolated from 31 participants, of which 15 (41.7%) were Escherichia coli and 8 (22.2%) Klebsiella pneumoniae. All isolates were susceptible to amikacin and tigecycline but an alarmingly high percentage (38.9%) were non-susceptible to colistin. A very high proportion of the CPE harbored blaKPC (58.3%), followed by blaOXA-48 (25%), blaNDM (5.6%) and blaVIM (2.8%). Carbapenemases were co-produced with ESBLs in 30.6% of the isolates. Sequencing of the KPC revealed that KPC-18 represented 45%, KPC-2 36% and KPC-29 18%. Considerable genetic diversity among the isolates was identified by MLST assays demonstrating the emergence of new clones. Five diverse new CPE clones were detected from three Bangladeshi citizens and 2 Indians.

Conclusion

Our finding demonstrates a relatively high colonization rate (8.9%) of healthy food handlers by CPE of which KPC-producing CPE were predominant; this is an unusual finding in Kuwait representing the first of such findings in our country and GCC.

Disclosures

All authors: No reported disclosures.