bluuebunny/crossref_metadata_2025_split huggingface dataset:
1383. In vivo Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of NOSO-502, a First-in-Class Odilorhabdin Antibiotic, Against E. coli (EC) and K. pneumoniae (KPN) in the Murine Neutropenic Thigh Model
Authors: Zhao Miao , Lepak Alexander J , Andes David R 
Published: November 2018

Abstract

Background
NOSO-502 is a novel, first-in-class Odilorhabdin antibiotic targeting bacterial protein translation, with potent in vitro activity against Enterobacteriaceae including strains with MDR or CRE-phenotype. The goal of this study was to determine the PK/PD characteristics of NOSO-502 using the murine thigh infection model against a diverse group of EC and KPN strains.

Methods
Twelve strains (6 EC, 6 KPN) were utilized, including those with tetracycline or β-lactam resistance. MICs were determined by CLSI Methods. Single dose murine plasma PK of NOSO-502 was determined after administration of 7.81, 31.25, 125 and 500 mg/kg by SC route. Dose fractionation (DF) study was used to determine which PK/PD index was associated with efficacy. The relationship between each PK/PD indices and CFU outcome data were analyzed using the sigmoid Emax (Hill) model with nonlinear regression. Treatment studies were then performed with the remaining 11 strains. Four-fold increasing NOSO-502 doses (3.91–1,000 mg/kg/6 hours SC route) were administered. Treatment data and AUC/MIC was analyzed to determine AUC/MIC targets associated with net stasis and 1-log kill (when achieved) for all strains.

Results
MICs ranged from 1 to 4 mg/L. PK ranges for doses included: Cmax 1.5–85 mg/L, AUC0-∞ 1.9–352 mg hour/L, T1/2 0.4–1.1 hour. DF regression analysis: AUC/MIC R2 0.86, Cmax/MIC R2 0.70, T &gt; MIC R2 0.77. Against each of the 12 strains there was dose-dependent activity and net stasis was achieved against all strains, with maximal activity of 1–2 log killing in EC and almost 3 log killing in KPN. The 24 hours stasis total and free drug PD targets are shown (table). 1-log kill targets were determined for KPN and noted at a median 24 hours fAUC/MIC of 11.

Conclusion
NOSO-502 demonstrated in vivo potency against a diverse group of EC and KPN strains including those with resistance to tetracycline and β-lactams. The PK/PD index predictive of efficacy is AUC/MIC. Stasis 24 hours AUC/MIC targets were numerically low for KPN and EC. This data suggest that NOSO-502 is a promising novel agent and these targets will provide a basis for developing human dosing regimens to optimize efficacy.

Disclosures
M. Zhao, Nosopharm: Research Contractor, Research support. A. J. Lepak, Nosopharm: Research Contractor, Research support. D. R. Andes, Nosopharm: Research Contractor, Research support.
1394. A Translational Pharmacokinetic Rat Model of Cerebral Spinal Fluid (CSF) and Plasma Concentrations of Cefepime
Authors: Liu Jiajun , Avedissian Sean , Pais Gwendolyn , Joshi Medha , Rhodes Nathaniel J , Scheetz Marc H 
Published: November 2018

Abstract

Background
For treatment of central nervous system infections caused by GNB, adequate cefepime concentrations are required in the cerebral spinal fluid (CSF) and brain. However, high plasma cefepime exposures have resulted in neurotoxicity. There is a need to understand the real-time pharmacokinetic (PK) relationship between plasma and CSF concentrations as serial CSF sampling is not regularly performed.

Methods
Male Sprague-Dawley rats received cefepime via an internal jugular vein catheter. A total daily dose of 150 mg/kg/day was administered as a single injection every 24 hours for 4 days. Plasma samples (mean n = 5 per rat) was obtained via a second dedicated catheter, with up to five samples obtained on a single concentration–time curve. CSF sampling occurred via an intracisternal catheter, with up to two samples taken every 24 hours. Cefepime in plasma and CSF were quantified via LC–MS/MS. PK analyses were conducted using Pmetrics for R. Multiple physiologic compartmental models were fit, with the ultimate model selected by Akaike score and rule of parsimony. Each rat’s concentrations were predicted from the final model, and predictive performance was evaluated with bias and imprecision of the population and Bayesian posterior prediction models. PK parameters were estimated, and PK exposures during the first 24 hours (i.e., AUC0–24, CMAX0–24, CMIN0–24) were calculated for each rat from Bayesian posteriors.

Results
Eleven rats contributed PK data. A three-compartment model fit the data well [Figure 1: Plasma, Population (a) and Bayesian (b); Figure 2: CSF, Population (a) and Bayesian (b)]. Population median parameter values (CV%) for rate constant (Ke), volume central compartment (V1), volume CSF compartment (V3), rate to/from central/peripheral compartment (KCP, KPC), rate to/from central/CSF compartment (K13, K31) were: 5.04 hour−1 (43.4%), 0.069 L (39.24%), 0.28 hour−1 (52.11%), 17.42 hour−1(34.83%), 0.32 hour−1 (165.3), 0.31 hour−1 (79.89), respectively. Noncompartmental analysis of the Bayesian posteriors revealed a plasma median half-life, AUC0–24, CMAX0–24, and CMIN0–24 of 2.6 hours, 158.1 mg hour/L, 189.3 mg/L, and 0.0003 mg/L from the first dose.

Conclusion
Cefepime transit to the CSF is rapid and highly predictable in the rat model. This model will be highly useful for understanding neurotoxicity outcomes for cefepime.

Disclosures
J. Liu, Merck: Grant fund from Merck, Research grant.
1397. Comparative Efficacy of Human-Simulated Epithelial Lining Fluid (ELF) Exposures of Tedizolid (TZD) Against Methicillin-resistant Staphylococcus Aureus (MRSA) in Neutropenic (I−) vs. Immunocompetent (I+) Murine Models of Pneumonia
Authors: Kidd James M , Abdelraouf Kamilia , Nicolau David P 
Published: November 2018

Abstract

Background
TZD is an oxazolidinone with potent in vitro activity against Gram-positive pathogens, including MRSA. Limited data currently exist on the efficacy of TZD in the presence of neutropenia. Herein, we investigate the comparative efficacy of human-simulated ELF exposures of TZD against MRSA in I− and I+ murine models of pneumonia.

Methods
Four MRSA isolates with TZD broth microdilution MICs of 0.5 mg/L were studied. BALB/c mice in I− groups were made neutropenic with cyclophosphamide. Lungs of I− mice were inoculated intranasally with bacterial suspensions of 107 CFU/mL; a higher inoculum of 109 CFU/mL was required to induce infection in I+ mice. Single daily doses of TZD simulating human ELF exposures after doses of 200 mg q24h were determined in both I+ (40 mg/kg) and I− (32 mg/kg) models. Three hours after inoculation, human-simulated doses of TZD were administered q24h for up to 72 hours while control mice were vehicle dosed. A group of control and another of treatment (n = 6) per isolate were sacrificed at 24, 48, or 72 hours for lung harvest. Bacterial densities were determined by quantitative culture and averaged across all isolates. Mice that succumbed to infection before the scheduled time of sacrifice were included in the next group due for sacrifice. Changes in log10 CFU/lungs at 24 hours were compared with 0 hour controls.

Results
The average bacterial burdens at 0 hour were 5.86 ± 0.21 and 8.10 ± 0.24 log10 CFU/lungs among I− and I+ mice, respectively. At 24 hours, average burdens in control mice were comparable among I− and I+ mice at 7.91 ± 0.62 and 9.01 ± 0.69 log10CFU/lungs, respectively. Mean changes in bacterial density are reported in the table. No I+ control mice survived past 48 hours.

Conclusion
Human-simulated ELF exposures of TZD demonstrated substantial and sustained efficacy in both I− and I+ murine models of pneumonia. These preclinical data utilizing clinically achievable bronchopulmonary exposures suggest that the efficacy of TZD for treatment of MRSA lung infections is not compromised by neutropenic status of the host. Further validation of these findings in patients is warranted.

Disclosures
D. P. Nicolau, Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Speaker honorarium.
344. Post Malaria Neurological Syndrome: A Rare Complication of Malaria
Authors: Yadava Sanjay , Fazili Tasaduq , Laleker Ashley , Poudel Pooja 
Published: November 2018

Abstract

Background
Post malaria neurological syndrome (PMNS) is a rare neurological complication that can occur after recovery from malaria, usually following severe Plasmodium falciparum malaria. A total of 43 cases have been previously reported in the literature.

Methods
We report a patient with neurological symptoms following 1 month of clinical and microbiological resolution of severe falciparum malaria following treatment consistent with PMNS.

Results
A 24-year-old male presented with fever, confusion, dysarthria, and grand mal seizure. His recent medical history was significant for severe falciparum malaria with multiorgan dysfunction, including acute kidney injury after being noncompliant with antimalarial prophylaxis while working for the Peace Corps in Togo prior to falling ill. He fully recovered but still required dialysis, and returned to the United States. He presented to the hospital 1 month after his initial malaria infection. On physical examination, the patient was febrile to 38.9°C, lethargic and responsive only to painful stimuli. Signs of meningismus were absent. Computed tomography of head, abdomen and thorax were unrevealing. Magnetic resonance imaging of the brain revealed a nonspecific focus of signal abnormality in right internal capsule. Cerebral spinal fluid (CSF) analysis revealed WBC of 75/μL, with lymphocytic pleocytosis and elevated protein of 65 mg/dL. CSF bacterial and viral polymerase chain reaction pane and cryptococcal antigen were negative. CSF VDRL was nonreactive. HIV antigen/antibody serology was negative. Blood, CSF, and urine cultures were all negative for growth. Two malaria smears were negative. Initially, he was started on broad spectrum antibiotics, Acyclovir and Coartem which were discontinued following negative laboratory results, and a steroid taper was initiated. His mental status began improving on the second day of the initiation of the steroid taper, and he fully recovered by day 5 of steroid therapy.

Conclusion
In patient with recent medical history of malaria who presents with neuropsychiatric symptoms, clinicians must have a high index of suspicion for PMNS.

Disclosures
All authors: No reported disclosures.
666. Human Granulocytic Anaplasmosis and Ehrlichiosis Presenting to an Upstate New York Emergency Department
Authors: Waxman Michael , White Jennifer , Dufort Elizabeth M , Eichelman Abigale , Stellrecht Kathleen , Kennedy Jeffrey 
Published: November 2018

Abstract

Background
Human granulocytic anaplasmosis (HGA) is an increasingly common tickborne infection in the North-East United States. Statewide incidence of human cases of anaplasmosis in New York (excluding New York City) increased 407% from 2010–2017, with a corresponding increase in Anaplasma phagocytophilum prevalence in ticks. While previous observational studies have described the clinical features of HGA, there has been little documentation of HGA diagnosed in the emergency department (ED) setting.

Methods
Demographic and clinical data were extracted from electronic records of cases with a positive polymerase chain reaction (PCR) for HGA or the closely related clinical entity ehrlichiosis from 2016 to 2017. HGA and ehrlichiosis PCR were performed by the Albany Medical Center laboratory on patients treated in the ED. Basic descriptive analyses were performed.

Results
During the 2-year period, there were 37 cases of PCR-positive HGA and four cases of PCR-positive ehrlichiosis treated in the ED. Electronic data were available for extraction for 40 of these cases. Mean age was 54 years old (range 7–94 years). Thirty-four (85%) patients presented with fever, and 9 (23%) reported a tick bite or tick exposure. Twenty-two (55%) patients had leukopenia; 32 (80%) thrombocytopenia; 26 (65%) hyponatremia; 24 (60%) elevated transaminases; 38 (95%) at least one of these laboratory abnormality; and 13 (33%) all four laboratory abnormalities. Twenty-four patients (60%) were given the empiric diagnosis of a tickborne illness upon disposition from the ED, with 19 (48%) patients admitted to the hospital.

Conclusion
To our knowledge, this study represents the first description of patients diagnosed with HGA (and ehrlichiosis) in the ED setting. Because of the inherent testing bias, further study is needed to establish the true ED prevalence of HGA in highly endemic regions. Notably, only 23% reported either a tick bite or tick exposure, highlighting the need to consider this for diagnosis in patients presenting to the ED with consistent symptoms and laboratory findings in endemic areas. Further study might explore whether there exists a collection of laboratory findings that could accurately identify HGA in ED patients.

Disclosures
All authors: No reported disclosures.
667. An Emerging Tick-Borne Disease in Long Island, New York: Relapsing Fever Caused by Borrelia miyamotoi
Authors: Marcos Luis , Smith Kalie , Weinbaum Fredric , Spitzer Eric 
Published: November 2018

Abstract

Background
Suffolk County (Long Island, New York) reports annually the highest absolute number of tick-borne diseases in New York. A new Borrelia species, Borrelia miyamotoi which causes a relapsing fever, has been reported in New York recently. The aim of this study was to identify the number of cases of B. miyamotoi diagnosed in Suffolk county.

Methods
A retrospective chart review was performed in Stony Brook (SB) Medicine hospitals, SB University Hospital (the only tertiary medical center in Suffolk County) and Southampton Hospital (a major hospital in the east end of Suffolk County). Laboratory records were queried for a positive B. miyamotoi PCR test from blood or a positive IgG antibody with a B. miyamotoi-specific EIA that utilizes a recombinant GlpQ antigen (both tests performed in a commercial laboratory).

Results
Twenty-eight cases were positive for serology (IgG EIA; n = 19) or PCR (n = 9). None of the IgG-positive cases had a positive PCR result indicating that individuals were likely exposed to B. miyamotoi in the past. Of the nine PCR-positive cases (median age:67 years), eight were men, three were diagnosed in the outpatient clinic (33.3%) and six were diagnosed through the emergency department and required hospitalization (66.6%). Thrombocytopenia and transaminitis were common findings. Two-thirds of these nine cases were diagnosed in the period of 2016–2017 and one-third in the period, 2013–2015 (P = 0.17).

Conclusion
An increasing number of cases of B. miyamotoi were observed in Suffolk County during 2013–2017 and two-thirds required hospitalization. The real burden of this tick borne disease in Suffolk County and the rest of the state is unknown.

Disclosures
All authors: No reported disclosures.
671. Increased Disease Severity and Larger Household Size Among Hispanic Infants With Pertussis: Chicago, IL, 2010–2016
Authors: Ramirez Enrique , Arwady Allison , Ruestow Peter , Fricchione Marielle 
Published: November 2018

Abstract

Background
Infants experience higher pertussis incidence and mortality compared with other age groups and 85% of infant cases are acquired from a household member. The Chicago Department of Public Health (CDPH) noted increased pertussis incidence among Hispanics from 2014 (5.3 cases per 100,000 population) to 2016 (12.3 cases per 100,000 population) while other ethnicities remained stable.

Methods
All pertussis cases reported to CDPH through the Illinois National Electronic Disease Surveillance System with onsets from January 1, 2010 to December 31, 2016 were included in the analyses. Variables of interest were age, race/ethnicity, household size, disease severity, healthcare location of diagnosis, and hospitalization. To assess differences in demographic and care-related indicators between Hispanic and non-Hispanic White (NHW) infants, chi-square tests were performed; risk ratios and 95% confidence intervals were estimated.

Results
From 2010–2016, 1,036 pertussis cases were reported to CDPH including 276 infants aged &lt;1 year. Among infant cases, 187(68%) were &lt;4 months of age, 143(52%) male, 151(55%) were Hispanic and 54(20%) were NHW. Median household size for infants of all ethnicities was four members (range: 0–15). Of all infants with household member size of ≥4 persons (157), 64% were Hispanic. 185 (67%) of infants had ≥1 severe symptom (apnea, cyanosis, pneumonia, seizure, encephalopathy) and 133 (48%) were hospitalized. Diagnosis occurred in the emergency room (ER) for 199 (72%) infants. Hispanics were more likely than NHW to have household member size ≥4 (RR 1.9, P &lt; 0.05), severe symptoms (RR 1.6, P &lt; 0.05), hospitalization (RR 2.3, P &lt; 0.05), and diagnosis in the ER (RR 2.8, P &lt; 0.05) (Table 1).

Conclusion
Among Chicago infant pertussis cases, Hispanic infants have larger household sizes and more severe disease at time of diagnosis compared with NHW.

Disclosures
All authors: No reported disclosures.
679. Mass-Scale Post-Hurricane Sheltering of Evacuees From Hurricane Harvey: Infectious Disease Surveillance and Prevention: Dallas County, Texas, 2017
Authors: Chung Wendy , Shim Kyoo , Blackwell James , Henderson Joel , Stocks Meredith , Richardson Folasuyi , Hughes Sonya , Ward Michelle 
Published: November 2018

Abstract

Background
The record rainfall following Hurricane Harvey’s landfall along the Texas coast on August 25, 2017 caused prolonged, widespread flooding, which devastated Houston and areas along the southern Gulf Coast. With shelters in Houston at capacity, residents from adjacent affected regions were evacuated elsewhere, and Dallas received over 3,800 evacuees at a single convention center shelter. Approaches to infectious disease surveillance and prevention in this mega-shelter setting were assessed and refined during the response.

Methods
Teams of epidemiologists and medical students reviewed all clinical records daily from the on-site, 24/7 walk-in medical clinic, which was staffed by local volunteer physicians. Demographic data, chief complaints, and diagnosis for each patient visit were reviewed, and daily aggregate summaries of visits for potential communicable disease symptoms were compiled. An additional infection control team consisting of health department staff and volunteer hospital infection preventionists implemented aggressive infection prevention measures in the shelter and clinic.

Results
Of the evacuees registered at this mass-scale shelter, 92% were from counties outside of Houston and 36% were 18 years of age or younger. During the shelter’s 23 days of operation, the shelter medical clinic received a cumulative volume of 2,654 clinic visits from 1,560 evacuees. The most common reasons for clinic visits included: need for medication refills (27.2%); respiratory symptoms (18.8%); and skin-related complaints (8.6%). Isolated cases of scabies, lice, norovirus, and influenza were confirmed, with no outbreak transmission of communicable diseases reported in the shelter.

Conclusion
The need for acute-care medical services and resources at a central shelter location was highlighted by the high proportion (40%) of evacuees seeking care at least once at the shelter medical clinic. The 24/7 accessibility of this on-site medical clinic to evacuees additionally provided a reliable mechanism for daily syndromic surveillance for potential outbreaks of infectious disease in a large shelter. Given the challenges of mass-sheltering and provision of clinical care in non-residential structures, dedicated staffing with infection control expertise was critical in this shelter setting.

Disclosures
All authors: No reported disclosures.
684. Risk Stacking for Pneumococcal Disease in Costa Rica
Authors: Chaverri-Murillo Jorge , Ramírez-Cardoce Manuel , Castro-Cordero José 
Published: November 2018

Abstract

Background
The value of nontraditional high-risk factor stacking is not known in the Costa Rican population. We aim to describe risk factor stacking for pneumococcal disease (PD) in patients seeking care at Social Security Hospitals in Costa Rica

Methods
Descriptive study of adult patients with microbiological culture-positive Streptococcus pneumoniae disease seeking care at two tertiary hospitals in Costa Rica between years 2014 and 2016. Information on underlying comorbidities (nontraditional) and other risk factors for PD was analyzed and stalked for each age group (G1: &lt;50, G2: 50–64, and G3: ≥65 y/o).

Results
We included 181 culture-positive patients. We found that patients in G1 predominantly stacked ≥2 risk factors (63%), the proportion of patients with ≥2 risk factor was similar to high-risk patients in G2 (33% vs. 38%). In G3, 18% didn’t stacked any other risk factor and 46% was on high-risk. Most frequent risk factors in G1/G2 were smoking and alcoholism, and in G3 chronic pulmonary and heart diseases.

Conclusion
We conclude that risk factor stacking is more relevant than high-risk conditions and PD also occurs in persons &lt;50 y/o. We recommend that risk factor stacking should be considered in prevention strategies for PD.

Disclosures
All authors: No reported disclosures.
685. Correlation Between Hospitalized Influenza and Group A Streptococcus Infections in Minnesota, 2010–2016
Authors: Arogbokun Olufunmilayo , Bell Austin , Abidoye Babatunde , Como-Sabetti Kathryn , McMahon Melissa , Lynfield Ruth 
Published: November 2018

Abstract

Background
Outbreaks of influenza can result in significant morbidity, including secondary bacterial infections. Invasive group A streptococcal (iGAS) infections are associated with a 12% case fatality rate. We used surveillance data to examine if there was a correlation between hospitalized influenza and GAS cases.

Methods
Minnesota Department of Health conducts population-based surveillance for hospitalized lab-confirmed influenza and iGAS (sterile site isolation) cases in the Minneapolis–St. Paul area as part of the CDC Emerging Infections Program. Cases were categorized by week during October–April of each year for 2010–2016, based on specimen collection date. Using STATA (v15), the correlation between the number of influenza (N = 11,768), and overall iGAS (N = 687), iGAS septic shock (n = 104), and iGAS pneumonia cases (n = 59) was assessed in weekly time periods using the Granger causality test.

Results
The number of hospitalized influenza cases was associated with an increase in the overall number of iGAS cases (Wald χ2 = 10.22, P = 0.04). Hospitalized influenza cases were associated with an increase in iGAS septic shock cases; every 1,000 increase in case counts were associated with one case of iGAS septic shock 1 week later (P = 0.02). Similarly, every 1,000 increase in hospitalized influenza cases were associated with one case of iGAS pneumonia 1 week later (P &lt; 0.01). While the effect of Granger causality is cumulative when describing the causal relationship between hospitalized influenza and total iGAS, the correlation between influenza and the iGAS subgroups is best described with a 1-week lag.

Conclusion
Granger causality tests are commonly used in economic modeling but have not been routinely applied to infectious diseases. Using this test, we found a strong correlation between weekly cases of hospitalized influenza and iGAS cases, with a 1-week lag between influenza and iGAS septic shock or pneumonia. This approach can provide insight into the potential impact of developing prevention interventions for infections with strong correlation. Further exploration of Granger tests in infectious disease modeling should be considered.

Disclosures
All authors: No reported disclosures.