bluuebunny/crossref_metadata_2025_split huggingface dataset:
167. A Bordetella pertussis Human Challenge Model Induces Immunizing Colonization in the Absence of Symptoms
Authors: De Graaf Hans , Ibrahim Muktar , Hill Alison , Gbesemete Diane , Gorringe Andrew , Diavatopoulos Dimitri , Kester Kent , Berbers Guy , Faust Saul , Read Robert 
Published: November 2018

Abstract

Background
Bordetella pertussis is one of the leading causes of vaccine preventable death and morbidity globally. Over the last 20 years, pertussis has resurged worldwide, even in territories with high immunization coverage. To improve vaccine strategies, a greater understanding of human B. pertussis infection and immunity is required. This study aims to develop a safe controlled human B. pertussis infection model and to define natural immune responses against wild-type B. pertussis in order to facilitate the development of bioassays and next-generation pertussis vaccines.

Methods
In this first-in-human controlled infection model, healthy volunteers aged 18–45 years with an anti-pertussis toxin (PT) IgG level of &lt;20 IU/mL were inoculated intranasally with B. pertussis strain B1917. Safety, colonization, and shedding were monitored over a 17-day inpatient period. Colonization was assessed by culture and qPCR of nasal washes and nasopharyngeal swabs. Azithromycin eradication therapy was commenced on day 14. The dose of inoculum was escalated to optimize colonization rate, expressed as the percentage of volunteers colonized at any sampling point between day 3 and 14. The immunological response is being assessed at various time points over 1 year.

Results
24 volunteers were challenged in groups of 4–5. The dose was gradually escalated from 103 colony forming units (cfu) to 105 cfu. Colonization rate ranged from 0% (dose 103 cfu) to 80% (105 cfu). Amongst this initial cohort, no significant safety concerns or symptoms attributed to B. pertussis disease were reported. Eradication was achieved by 48 hours in 100% of colonized volunteers. At least 4-fold rise in anti-PT IgG by day 28 in comparison to baseline was observed in 5 out of 8 volunteers who had &gt;1,000 cfu/mL viable B. pertussis in the nasal wash and in one volunteer without detectable colonization. Nasal wash cultures were more sensitive in detecting colonization than nasopharyngeal swab cultures. No shedding of B. pertussis was detected in systematically collected environmental samples.

Conclusion
This is the first study to demonstrate safe deliberate induction of B. pertussis colonization. It shows that asymptomatic B. pertussis colonization occurs and causes a systemic immune response. The model that we have developed will be a valuable tool to further investigate B. pertussis colonization and vaccine development.

Disclosures
K. Kester, Sanofi: Employee, Salary. S. Faust, Pfizer, Merck, Sanofi, AstraZeneca/Medimmune: Scientific Advisor, all honoraria paid to institution with no personal payments of any kind.
168. Intradermal Immunization Drives Humoral and Cellular Immunity to the Lung and Protects Against Acute P. aeruginosa Pneumonia
Authors: Baker Sarah , Morici Lisa 
Published: November 2018

Abstract

Background
Pseudomonas aeruginosa is a leading cause of hospital-associated pneumonia, with 6,700 multidrug-resistant infections in the US annually. Evidence suggests that antibodies and CD4 Th1 and Th17 responses contribute to protection against P. aeruginosa infection. Recent work suggests that intradermal (ID) immunization with a vaccine adjuvanted with a double mutant of E. coli heat-labile toxin (dmLT) can direct protective immune responses to mucosal tissues such as the lungs. We sought to determine whether ID immunization with P. aeruginosa outer membrane proteins (OMPs) with dmLT could drive migration of CD4+ T cells and antibodies to the lungs and protect against P. aeruginosa pneumonia.

Methods
We immunized C57Bl/6 mice with 1 µg of OMPs with 1 µg dmLT. Control mice received OMPs or saline. Antibody and T-cell responses were assessed by ELISA and flow cytometry, respectively. We then evaluated the protective efficacy of the vaccine in a lethal acute pneumonia model. Immunized mice were challenged with 7 × 106 CFU of P. aeruginosa via oropharyngeal aspiration into the lungs. Finally, we examined whether memory CD4+ T cells was essential for protection by depleting immunized mice of vaccine-induced memory CD4+ T cells.

Results
Mice immunized with OMPs and dmLT had a significantly greater concentration of anti-pseudomonal IgG in the serum and lungs and a significantly greater proportion of CD4+ T cells in the lung producing IFN-γ or IL-17A than mice immunized with OMPs alone or saline. ID immunization provided significant protection against P. aeruginosa pneumonia, with 78% of immunized mice surviving compared with 100% mortality in saline immunized controls. Memory CD4+ T-cell–depleted mice displayed reduced survival (40%) compared with nondepleted mice (80%), confirming that memory CD4 T+ cells contribute to OMP-dmLT vaccine-mediated protection.

Conclusion
These results demonstrate that ID vaccination against P. aeruginosa protects against acute lethal P. aeruginosa pneumonia by stimulating antigen-specific IgG and Th1- and Th17-type CD4+ memory T cells in the pulmonary milieu. ID immunization with dmLT may reduce the global morbidity and mortality caused by multidrug-resistant respiratory pathogens.

Disclosures
All authors: No reported disclosures.
865. Acanthamoeba Disease Associated With the Practice of Nasal Rinsing in Immunocompromised Patients
Authors: Cope Jennifer , Roy Shantanu , Ali Ibne 
Published: November 2018

Abstract

Background
The genus Acanthamoeba are free-living amebae found worldwide in water, including tap water, and soil that can cause rare but severe infections of the eye, skin, and central nervous system. Acanthamoeba spp. generally cause disease in immunocompromised persons, including those with HIV, hematologic malignancies, and solid organ transplants. The route of transmission and incubation period are not well known in humans, but animal studies have shown that disease can be produced via the intranasal, intrathecal, and intravenous routes. We describe 5 cases of Acanthamoeba disease among immunocompromised patients who practiced nasal rinsing prior to becoming ill.

Methods
The Centers for Disease Control and Prevention (CDC) offers a clinical consultation service for free-living ameba infections and maintains a Free-living Ameba laboratory with confirmatory diagnostic testing capabilities. When an Acanthamoeba case is confirmed in the United States, details about the case are collected on a standardized case report form which includes questions about the case–patient’s water and soil exposure prior to becoming ill. Questions about nasal rinsing were added to the form in 2011.

Results
Five Acanthamoeba case patients in CDC’s free-living ameba database were reported to have performed nasal rinsing prior to becoming ill. The median age was 60 years (range 36–73 years) and 3 of 5 patients were female. Two were solid-organ transplant patients (heart and kidney), 2 had chronic lymphocytic leukemia, and 1 had HIV. Three patients presented only with encephalitis and died. The 2-organ transplant patients had a combination of rhinosinusitis, osteomyelitis, and skin lesions. One survived and the other died, the cause of which was unrelated to Acanthamoeba. All reported using tap water to perform nasal rinsing, most for sinus congestion using a neti pot or similar device and one for religious purposes.

Conclusion
Acanthamoeba is an inhabitant of water, including treated tap water. Immunocompromised patients, like those presented here, might be at risk for infections caused by Acanthamoeba transmitted via tap water used for nasal rinsing. Clinicians caring for immunocompromised patients should advise their patients not to use tap water for nasal or sinus rinsing.

Disclosures
All authors: No reported disclosures.
918. Typhoid Fever in the US Pediatric Population, 1999–2015, and the Potential Benefits of New Vaccines
Authors: McAteer Jarred , Derado Gordana , Hughes Michael , Bhatnagar Amelia , Medalla Felicita , Chatham-Stephens Kevin , Appiah Grace D , Mintz Eric D 
Published: November 2018

Abstract

Background
In the United States, typhoid fever is rare. About 300 typhoid cases are reported to CDC annually through the National Typhoid and Paratyphoid Fever Surveillance (NTPFS) system. Most are acquired during international travel and while visiting friends and relatives. CDC recommends pretravel vaccination of at-risk children with one of two currently available vaccines: oral (age ≥6 years) or injectable (age ≥2 years). In anticipation of licensure of new protein-conjugate typhoid vaccines that could be administered to children ≥6 months old, we characterized clinical, epidemiologic, and antimicrobial resistance data of pediatric typhoid fever cases reported to CDC.

Methods
We reviewed laboratory-confirmed Salmonella enterica serotype Typhi infections reported to NTPFS and antimicrobial resistance data on Typhi isolates in the National Antimicrobial Resistance Monitoring System (NARMS) from 1999 to 2015.

Results
Of 2,051 pediatric (≤18 years) cases of typhoid fever, 80% had traveled internationally within 30 days of illness onset (most frequently to South Asia [82%]), 81% were hospitalized (median duration 6 days; range 0–77 days), and none died. Eight hundred twenty-seven (40%) were &lt;6 years old; 219 (26%) were 6 months–2 years old. While 76% of pediatric cases were vaccine eligible (travelers ≥2 years old), only 6% were known to be vaccinated. Of 2,020 isolates tested for antimicrobial susceptibility, 1,211 (60%) had decreased susceptibility or resistance to ciprofloxacin, of which 277 (23%) were also resistant to ampicillin, chloramphenicol, and trimethoprim/sulfamethoxazole (multidrug-resistant [MDR]). None were resistant to ceftriaxone or azithromycin. MDR isolates were more likely in children than adults (16% vs. 9%, P &lt; 0.05) and in travel-associated than domestically acquired cases (16% vs. 6%, P &lt; 0.05).

Conclusion
Among pediatric cases of typhoid fever, 94% of currently vaccine-eligible travelers were unvaccinated. Emphasis on current vaccine indications and an effective pretravel typhoid vaccine for children between 6 months and 2 years old available during routine immunization visits could begin to reduce the burden of disease, and help prevent drug-resistant infections, in this vulnerable age group.

Disclosures
All authors: No reported disclosures.
919. Clinical and Microbiologic Characteristics Associated With Long-Term Orthopedic Complications Following Staphylococcus aureus Acute Hematogenous Osteoarticular Infections in Children
Authors: McNeil J Chase , Kok Eric , Sommer Lauren , Vallejo Jesus G , Hulten Kristina G , Kaplan Sheldon L 
Published: November 2018

Abstract

Background
Staphylococcus aureus is the most common cause of acute hematogenous osteoarticular infections (AHOAIs) in children. While the vast majority of patients do well, a small proportion experience significant morbidity, including chronic infection and pathologic fractures. We sought to describe clinical and microbiologic variables present on the index admission that may predict long-term orthopedic complications (OC).

Methods
Cases of S. aureus AHOAI were identified from 2011 to 2016 at Texas Children’s Hospital (TCH). All cases were reviewed for the development of OC until April 1, 2018. OC included chronic osteomyelitis (CO), growth arrest/limb length discrepancy, avascular necrosis, chronic dislocation, and pathologic fracture (PF) with or without angular deformity. All S. aureus isolates were characterized by PCR for Panton–Valentine Leukocidin (PVL) genes and agr group. Statistical Analyses were performed with STATA.

Results
A total of 252 cases were identified meeting inclusion criteria (figure). Twenty-four (9.5%) developed OC; of which, 50% were CO and 25% PF. Patients who developed CO more often had positive blood cultures during the index admission (P &lt; 0.001), surgical drainage after hospital day 2 (33.3% vs. 8.8%, P = 0.02) as well as a longer time to 50% reduction in C-reactive protein (CRP, 9 vs. 7 days, P = 0.01). Patients who developed PF more often had infection due to PVL-positive organisms (83.3% vs. 38.6%, P = 0.03) and had a longer duration of fever after admission (9.5 vs. 2.5 days, P = 0.03). Overall, OC were associated with ICU admission (P = 0.04), a slower decline in CRP (P = 0.02) and a greater proportion of patients with surgery after hospital day 2 (P = 0.04) as well as infection secondary to agr III isolates (P = 0.03). There was no statistically significant relationship between OC and patient age, affected bone, time to initiation of effective antimicrobial therapy, duration of intravenous therapy, or final antibiotic choice.

Conclusion
Patients with S. aureus AHOAI with a delay in source control, slow decline in CRP, prolonged fever or ICU admission are at higher risk of OC. While nonspecific, these findings suggest that such patients may warrant especially cautious clinical follow-up to identify sequelae early. Large multicenter studies are needed to better predict OC in this setting.

Disclosures
All authors: No reported disclosures.
921. Antibiotic Prescribing for Children in Family Medicine Clinics Within a Practice Research Network
Authors: Poole Nicole , Kronman Matthew , Gerber Jeffrey S , Baldwin Laura-Mae , Zerr Danielle 
Published: November 2018

Abstract

Background
Family medicine clinics provide care for one-third of US children, yet comprehensive data about antibiotic prescribing in this patient population are lacking. We aimed to characterize antibiotic prescribing for children in family medicine clinics.

Methods
A retrospective cohort of patients aged 0–17 years with a visit to a family medicine clinic within the Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) Region Practice and Research Network (WPRN) from January 1, 2014 to April 30, 2017 was studied. Patients with complex chronic conditions were excluded. We defined narrow-spectrum antibiotics as penicillin, amoxicillin, first-generation cephalosporins, sulfonamides, and nitrofurantoin; and broad-spectrum antibiotics otherwise. On the basis of national guideline recommendations and a previously published hierarchical classification system, we assigned diagnoses to one of the 3 tiers: diagnoses for which antibiotics were (1) almost always indicated (e.g., bacterial pneumonia), (2) may be indicated (e.g., pharyngitis), and (3) generally not indicated (e.g., bronchiolitis/bronchitis).

Results
We studied 20,779 pediatric patients with 97,228 clinic visits. Oral antibiotics were prescribed in 10,922 (11%) of all encounters. The median rate of antibiotic prescribing among providers was 14% (interquartile range: 4.9%–18.5%). Of all antibiotics prescribed, 51% were broad-spectrum agents. Acute respiratory tract infections (ARTIs) accounted for 67% of all antibiotics prescribed. Of the antibiotics prescribed for ARTI, 25% were for diagnoses where antibiotics are generally not indicated. First-line guideline-recommended antibiotics were prescribed in 80% of acute otitis media, 80% of sinusitis, 68% of pharyngitis, and 31% of community acquired pneumonia diagnoses. Azithromycin monotherapy was prescribed in 52% of community acquired pneumonia diagnoses.

Conclusion
Specific targets for improving antimicrobial prescribing within a family medicine practice research network include prescribing of broad-spectrum antibiotics (particularly azithromycin), prescribing for conditions where antibiotics are not indicated, and first-line guideline-recommended prescribing for pharyngitis and community acquired pneumonia.

Disclosures
All authors: No reported disclosures.
927. Tap Water Avoidance Decreases Rates of Nontuberculous Mycobacteria in Intensive Care Units
Authors: Baker Arthur W , Smith Becky , Sexton Daniel J , Huslage Kirk , Stout Jason E , Anderson Deverick J , Moehring Rebekah W , Hostler Christopher , Lewis Sarah S 
Published: November 2018

Abstract

Background
We recently investigated a clonal outbreak of Mycobacterium abscessus molecularly linked to a colonized water supply at a new hospital addition. Use of sterile water instead of tap water for patient care in ICUs successfully mitigated the respiratory phase of the outbreak. We hypothesized that avoidance of tap water would also be associated with decreased respiratory isolation of other nontuberculous mycobacteria (NTM).

Methods
We analyzed all positive cultures for NTM obtained at our hospital from August 2013 through December 2015. The pre-intervention outbreak period was defined as August 2013 through May 2014; the tap water avoidance intervention period was defined as June 2014 through December 2015. NTM isolation was defined as a positive culture from a respiratory specimen obtained from an ICU patient on day 3 or later of hospitalization. We also performed AFB cultures of biofilms obtained from ICU water sources.

Results
NTM were isolated from 137 patients during 70,168 patient-days (figure). NTM isolation decreased from 41.0 patients/10,000 patient-days in the outbreak period to 9.9 patients/10,000 patient-days in the intervention period (IRR, 0.24; 95% CI, 0.17–0.34; P &lt; .0001) (table). Incidence rates of the 4 most common NTM (M. abscessus, M. chelonae/immunogenum, M. avium complex, and M. gordonae) also markedly decreased. Biofilm cultures were positive for at least 1 NTM isolate in 25 of 33 (76%) ICU water sources, including M. abscessus (n = 11, 33%), M. chelonae/immunogenum (n = 11, 33%), and M. gordonae (n = 11, 33%).

Conclusion
The use of sterile water for ICU patient care substantially decreased NTM isolation from patient respiratory specimens, presumably reducing risk of symptomatic infection. Hospitals with endemic NTM should consider tap water avoidance for high-risk patients.

Disclosures
All authors: No reported disclosures.
962. Cutaneous Leishmaniasis: Investigating Skin Drug Levels to Optimize Liposomal Amphotericin Dosing
Authors: Aronson Naomi E , Koles Nancy , Moran Sean , Zhang Aihong 
Published: November 2018

Abstract

Background
Liposomal amphotericin B (L-amB, AmBisome®) is popular for off-label use in the treatment of cutaneous leishmaniasis (CL) using dosing of 3 mg/kg/day for days 1–5, 8, 9, or days 1–5, 10 with reported clinical cure rates of 46–84%. In rodents, the skin concentration of L-amB is 40-fold less than that in visceral organs. We hypothesize that a specific L-amB regimen targeted to skin concentrations could maximize a beneficial treatment response in CL.

Methods
SKH1 477 Elite hairless mice (Charles River), 5 per group, received intravenous L-amB at doses of (A) 3 mg/kg/day for days 1–5, 8, 9, (B) 5 mg/kg/day for 4 days, (C) 10 mg/kg load than 5 mg/kg/day for 3 days, (D)10 mg/kg/day for 2 days, (E) 15 mg/kg/day for 2 days. Serum and skin (back) punch biopsies were collected on day 0, 2, 5, 14, and 21. Nasal mucosa was biopsied on day 21. Tissue samples were homogenized and L-amB was extracted with methanol and acetonitrile. Liquid chromatography–mass spectrometry was performed using these extracted samples on an Agilent 1200 series HPLC and an AB Sciex Q-Trap 4000 mass spectrometer. Experiment conducted twice for confirmation.

Results
L-amB doses were well tolerated by the mice, except weight loss was seen in regimen E. Day 21 serum L-amB levels were 82 ± 3.2 (ng/mL) regimen A, 91 ± 4.2 in B, 89 ± 4 in C, 118 ± 3.7 in D, 98 ± 1.5 in E. Mean L-amB nasal tissue levels on day 21 were 1.33 + 3.2 (ng/mg tissue) regimen A and 6.5 ± 3 in D (P = 0.031). Mean L-amb skin levels on day 14 were 8.4 ± 5.6 (ng/mg tissue) in regimen A, 4.0 ± 1.7 in B, 6.2 ± 3.3 in C, 13.9 ± 7.1 in D, 33.9 ± 24.7 in E. Skin L-amB levels at day 21 were less than 5 (ng/mg tissue) except for regimen D 9.3 ± 4.2 and regimen E 7.8 ± 2.6. SKH1 477 Elite mice did not permit an adequate Leishmania major infection (very tiny lesions when compared with other murine species) to correlate these results clinically in this specific murine model.

Conclusion
While regimens A–D received similar total dosages of L-amB, the skin and nasal mucosal levels were significantly higher in the short, high daily dose regimens compared with the L-amB regimen that is currently used in CL patients. This suggests that better clinical results might be seen by using a L-amB dosing regimen for CL of 10 mg/kg for 2 days, a dose regularly used in the treatment of pediatric visceral leishmaniasis.

Disclosures
All authors: No reported disclosures.
965. Applying Clinical Prediction Tools to Patients with Lassa Fever
Authors: Chiosi John , Shaffer Jeffrey , Schieffelin John 
Published: November 2018

Abstract

Background
Clinical prediction tools such as the Quick Sequential Organ Failure Assessment (qSOFA) and the Modified Early Warning Score (MEWS) have been used to predict mortality from sepsis in high-income countries, but their application to low- and middle-income countries have been limited. Lassa fever is a viral hemorrhagic fever endemic to West Africa with a case fatality ratio for hospitalized patients of up to 69%. The purpose of this study was to evaluate existing clinical prediction tools for critical illness in predicting adverse outcomes in patients with Lassa fever.

Methods
We conducted a retrospective cohort study of patients admitted to the Kenema Government Hospital Lassa ward in Sierra Leone between 2012 and 2017. Patients were required to meet the World Health Organization case definition for suspected Lassa Fever to be admitted to the ward. We included patients who had laboratory-confirmed Lassa fever via ELISA tests for Lassa Ag or IgM. Control samples were included with negative ELISA tests for Lassa Ag and IgM. We compared criteria for qSOFA, MEWS, Systemic Inflammatory Response Syndrome (SIRS), and Universal Vital Assessment (UVA) among the Lassa Ag+ (patients with acute viremia), Ag-/IgM+ (patients who cleared the virus and developed an immune response), and Ag−/IgM− (control) groups.

Results
There were 157 patients included in this preliminary analysis. Of patients in the Ag+ group, the mean age was 20.2 years and 40.8% were female. Patient demographics were similar among all groups. Clinical outcomes significantly differed among the groups, with the highest in-hospital mortality at 62.5% in the Ag+ group. For each clinical prediction tool, mean scores significantly differed among groups (P &lt; 0.05; see table). The highest scores were consistently seen in the Ag+ group.

Conclusion
Patients with acute viremia for Lassa fever had higher scores for clinical prediction tools compared with controls, which imply a higher risk of mortality. Additional research is needed on the sensitivity and specificity of these tools for mortality due to Lassa fever.

Disclosures
All authors: No reported disclosures.