bluuebunny/crossref_metadata_2025_split huggingface dataset:
1563. Population Pharmacokinetics and Pharmacodynamics of Daily and Extended Interval Dalbavancin Dosing Regimens for Salvage Therapy of Staphylococcus aureus Endocarditis: Mechanistic Modeling of Rabbit Infection Data to Support Human Dosing Regimens
Authors: Farkas Andras , Yassin Arsheena , Fantin Bruno , Lefort Agnes 
Published: October 2019

Abstract

Background
Dalbavancins’ (DAL) long half-life and favorable susceptibility profile makes it an attractive option for salvage therapy for endocarditis caused by Staphylococcus aureus (SA), including those with elevated vancomycin (VAN) MIC. The aim of our study was to establish the PKPD of DAL based on a rabbit model of infection and extrapolate those results to the design of human treatment regimens.

Methods
Data from a rabbit endocarditis model of SA with VAN MICs of 2 and 8 mg/L were fitted using an inoculum-size dependent model and the Pmetrics software. Then, the results were linked to a human PK model to simulate regimens with or without a loading dose. Probability of target attainment (PTAs) for achieving bacterial density of <2 log CFU per gram of vegetation was compared with outcomes based on standard antibiotic therapy (SAT) at 3, 10, 21, 31, and 42 days.

Results
Mean (SD) PTAs of 34.3% (10.5%), 61.3% (7.0%), 73.5% (5.4%), 79.5% (4.3%), and 83.1% (3.4%) were estimated for all regimens combined with maximum PTAs of 41.8%, 63.6%, 77.8%, 86.6%, and 88.9% for the highest weekly dose at 3, 10, 21, 31 and 42 days of therapy, respectively. While all approaches should achieve an adequate probability of clearing of the colonies by day 21, only doses near 2,000 mg/week are likely to approximate sterilization rates similar to that expected by the SAT at day 42. We observed no meaningful differences in PTAs for weekly vs. daily dosing given with a load. Also, increasing the total weekly dose over 2,000 mg seems to offer minimal additional benefit (Figure 1A–D). Trough-level accumulation is expected as total weekly doses increase, showing a median (IQR) of 62.6 (73.1,85.2) [101.8 (89.9,117.4)] mg/L and 106.5 (91.63,123.6) [135.3 (118.3,156.0)] mg/L at 42 days for the 1,000 mg and 1,500 mg weekly [in equal daily fractions] doses, respectively.

Conclusion
Our design suggests that these DAL dosing regimens in humans are likely to provide reasonable rates of sterilization when treating endocarditis caused by SA isolates, and administration of near 2,000 mg weekly doses may be considered to improve upon sterilizing effect, but at the cost of accumulating DAL levels. Efficacy and safety of new regimens should be confirmed in well-controlled clinical trials.

Disclosures
All authors: No reported disclosures.
1576. Delaying the Start of Maintenance Vancomycin After a Loading Dose to Avoid a High 0–24h AUC
Authors: Lee Judy T Y , Ebert Steven C 
Published: October 2019

Abstract

Background
Vancomycin dosing guidelines recommend loading doses (LDs) (25–30 mg/kg TBW), and a maintenance regimen, usually started after a time period equal to the dosing interval. Studies of vancomycin exposure and nephrotoxicity conclude that a 0 to 24-hour area under the serum concentration–time curve (0–24AUC) > 677 mg-hour/L results in a 3- to 4-fold increased risk of nephrotoxicity (Zasowski EJ, Antimicrob Agents Chemother 2018). For vancomycin LDs we compare the calculated LD and the maintenance dose, and delay initiation of the maintenance regimen when the LD exceeds the daily maintenance dose by > 50%. This study assessed the pharmacokinetic outcomes from this technique.

Methods
We retrospectively reviewed 68 consecutive adult patients receiving therapeutic doses of vancomycin. Patient age, sex, height, weight, serum creatinine, and indication were used to calculate the daily dose/intervals for a steady-state 24-hr AUC of 400 or 600 mg-hour/L. The total 0–24AUC was calculated by adding the 0–24 AUC from a 25 mg/kg LD (max: 3 gm) to the 0–24AUC(s) for maintenance dose(s) within the first 24 hours. We compared the total 0-24AUC when the first maintenance dose was timed for the next dosing interval (“scheduled”) to that when the maintenance dose was delayed according to our protocol (“delayed”). We tested the proportion of patients who would be exposed to a vancomycin 0-24AUC > 677 mg-hour/L.

Results
16/68 patients were diagnosed with SSTI (goal 24 hr AUC: 400 mg-hour/L) and 52/68 with sepsis, bacteremia/endocarditis, or pneumonia (24 hr AUC: 600 mg-hour/L). Median daily maintenance dose was 1750 mg (range: 875–4,000 mg). For patients with a goal AUC of 400, the 0-24AUC was > 677 mg-hour/L in one patient using the “scheduled” process and in none of the patients using the “delayed” protocol. However, for patients with a goal AUC of 600, the 0-24AUC was > 677 mg-hour/L in 22/52 patients via the “scheduled” process vs. 4/52 patients via the “delayed” protocol.

Conclusion
For patients with severe gram-positive bacterial infections requiring aggressive dosing of vancomycin, delaying the start of maintenance dosing following a large LD is an effective way to ensure attainment of goal therapeutic AUC within the first 24 hr without placing the patient at increased risk for nephrotoxicity.

Disclosures
All authors: No reported disclosures.
1579. Multidrug-Resistant Candida auris Isolates From New York Hospitals and Healthcare Facilities Are Susceptible to Antifungal Combinations
Authors: O’Brien Brittany , Chaturvedi Sudha , Chaturvedi Vishnu 
Published: October 2019

Abstract

Background
Candida auris outbreak continues unabated in New York with the current case counts exceeding 300 patients. We used a modification of standard CLSI broth microdilution method (BMD) if two-drug combinations are efficacious against C. auris isolates with high-resistance to fluconazole (FZ, MIC50 >256 mg/L), and variable resistance to other broad-spectrum antifungal drugs.

Methods
BMD plates were custom-designed and quality controlled by TREK Diagnostic System. The combination tests of 15 drug-resistant C. auris involved microtiter wells with the initial 144 two-drug combinations and their two-fold dilutions (1/2–1/32) to get 864 two-drug combinations finally. We utilized MIC100 endpoints for the drug combination readings as reported earlier for the intra- and inter-laboratory agreements obtained against Candida species and Aspergillus fumigatus (Antimicrob Agents Chemother. 2015. 59:1759–1766). We also tested minimum fungicidal concentrations (MFC).

Results
We tested all possible 864 two-drug antifungal combinations for nine antifungal drugs in use to yield 12,960 MIC100 readings, and MFC readings for 15 C. auris isolates. Flucytosine (FLC) at 2.0 mg/L potentiated most successful combinations with other drugs. Micafungin (MFG), Anidulafungin (AFG), Caspofungin (CAS) at individual concentrations of 0.25 mg/L combined well with FLC (2.0 mg/L) to yield MIC100 for 14, 13, and 12 of 15 C. auris isolates tested, respectively. MFG/FLC combination was also fungicidal for 4 of 15 isolates. AMB / FLC (0.25/1.0 mg/L) yielded MIC100 for 13 isolates and MFC for three test isolates. Posaconazole (POS), and Isavuconazole (ISA) and Voriconazole (VRC) also combined well with FLC (0.25/2.0 mg/L) to yield MIC100 for 12, 13, and 13 isolates, respectively. POS/FLC combination was fungicidal for three isolates.

Conclusion
We identified seven two drug-combinations of antifungals efficacious against drug-resistant C. auris strains. The modified BMD combination susceptibility testing could be used by the clinical laboratories to assist providers with the selection of optimal treatment for C. auris candidemia.

Disclosures
All authors: No reported disclosures.
1580. Colistin Potentiates the In Vitro Activity of Meropenem–Vaborbactam (M/V) Against Some, but not All KPC-producing Klebsiella pneumoniae (KPC-Kp)
Authors: Jones Chelsea E , Kline Ellen G , Nguyen Minh-Hong , Clancy Cornelius J , Shields Ryan K 
Published: October 2019

Abstract

Background
M/V demonstrates potent in vitro activity against KPC-producing organisms. It is unclear whether the combination interacts synergistically with other active agents.

Methods
We tested isolates for responses to M/V alone (1 and 4x MIC; V fixed at 8 µg/mL), and in combination with colistin (COL; 2 µg/mL), fosfomycin (FOS; 100 µg/mL + 25 µg/mL G6P), gentamicin (GEN; 2 µg/mL), and tigecycline (TGC; 2 µg/mL) by time-kill using a starting inoculum of 1 × 108 cFu/mL. 24h was the primary endpoint.

Results
16 KPC-Kp isolates were studied (7 KPC-2 and 9 KPC-3); all were M/V-susceptible (MIC range: 0.015 – 4 µg/mL). 44% harbored ompK36 mutations (4 IS5 promoter insertion, 2 134–135 DG duplication, and 1 premature stop codon). Median M/V MICs were higher against isolates with mutant ompK36 (0.25 vs. 0.03; P = 0.002). Mean log-kills by M/V at 1x and 4x were -0.50 and -2.41, respectively; M/V was bactericidal (≥3-log kill) against 6% and 56%, respectively (Figure 1). Mean log-kills at 4× were greater against KPC-2 (-3.79) than KPC-3 (−1.33) isolates (P = 0.09), and among isolates with (−3.31) vs. without (−1.71) ompK36 mutations (P = 0.11). GEN was the most active single agent (bactericidal against 56%, mean log-kill = −3.04). In combo with M/V, rates of synergy (>2-log kill in combo) with COL, FOS, GEN, and TGC were 44%, 19%, 12.5%, and 12.5%, respectively (Figure 2). Corresponding rates of bactericidal activity were 44%, 25%, 69%, and 31%, respectively. Antagonism (> 1-log kill by most active single agent) was identified for each combo against 2 isolates. Mean log-kills by M/V + GEN were greater against isolates with GEN MICs ≤1 (−7.16) vs. ≥2 (−1.66; P = 0.001), reflecting the activity of GEN alone. Mean log-kills by M/V + COL were greater against isolates with IS5 insertions (-6.32) compared with wild type (−2.38) or other mutations (−1.77) in ompK36. Responses to M/V + FOS were not dependent upon FOS MIC, but log-kills were greater against mutant (-2.13) vs. wild-type (0.01) ompK36 (P = 0.03).

Conclusion
M/V + GEN is rapidly cidal if GEN MICs are ≤1, while M/V + COL resulted in highest rates of synergy against diverse KPC-Kp. Mean log-kills were highest among isolates with IS5 promoter insertions suggesting a potential role for COL combination therapy against KPC-Kp isolates with decreased outer membrane permeability.

Disclosures
All authors: No reported disclosures.
1585. Isavuconazonium Sulfate plus Micafungin Improves Survival in an Immunocompromised Murine Model of Disseminated Fusariosis
Authors: Mavridou Eleftheria , Al-Saddah Nura , Mouskas Konstantinos , Naing Ethan , Abzalimov Rinat , Arbona Rodolfo J Ricart , Walsh Thomas J 
Published: October 2019

Abstract

Background
Disseminated fusariosis in patients with hematological malignancies is a frequently fatal and emerging invasive mycosis. Fusarium spp. are often resistant to safely achievable concentrations of mould active triazoles and amphotericin B. We aimed to determine the efficacy of isavuconazonium sulfate (ISA) alone or in combination with micafungin (MICA) in a murine model of disseminated fusariosis caused by Fusarium solani.

Methods
Groups of five 5-week-old Swiss Webster female mice, 20–22 g, were rendered neutropenic by intraperitoneal (IP) injection of cyclophosphamide at 200 mg/kg on day −2 and 150 mg/kg on day +3. Mice were infected with 5 × 10E5 CFU F. solani intravenously (IV) via the lateral tail vein on day 0. To prevent bacterial infection, ceftazidime was administered 50 mg/kg/day IP. Therapy began 18 h post-challenge for 6 days. MICA was given at dosages of 10, 5, 2.5 and 1.25 mg/kg IP Q12h combined with ISA 14 mg/kg/day IP. Six groups of mice received ISA orogastrically (OG) Q8h, Q12h and Q24h at 224 mg/kg alone or combined with MICA at 10 mg/kg Q12h IP. Kaplan–Meier survival analysis was performed.

Results
ISA at 14 mg/kg Q12h combined with 10 mg/kg MICA doses resulted in improved survival but with no significant reduction of residual fungal burden compared with monotherapy or other ISA/MICA dose combinations. Improved survival with dose-escalated oral monotherapy was observed at ISA 224 mg/kg Q12h (50% survival) and Q8h OG (60%) compared with other monotherapy or combination, or untreated groups (18–20%). The residual fungal burden in kidney between monotherapy and combination therapy groups was 5.81 10Log (untreated), 4.03 10Log (ISA 224 mg/kg, OG Q12h), 5.19 10Log (ISA 224 mg/kg Q12h + MICA 10 mg/kg, Q12h), 4.67 10Log (ISA 224 mg/kg, Q24h), and 4.82 10Log (ISA 224 mg/kg Q24h + MICA 10 mg/kg, Q12h).

Conclusion
High doses of isavuconazole (exceeding currently approved human dosages) in combination with micafungin improved survival in experimental murine disseminated fusariosis. Given the excellent safety profile of ISA, exploration of higher dosages that are necessary to achieve this antifungal effect is warranted for successful management of disseminated fusariosis.

Disclosures
All authors: No reported disclosures.
1614. Single-Dose Doxycycline as Lyme Disease Post-Exposure Prophylaxis in a National Commercial Insurance Claims Database―the United States, 2014–2017
Authors: Marx Grace E , Schwartz Amy M , On Camay , Hinckley Alison F 
Published: October 2019

Abstract

Background
Approximately 300,000 cases of Lyme disease occur annually in the UNITED STATES, with children aged 5–9 years disproportionately affected. A single dose of doxycycline administered within 72 hours of a high-risk tick bite is recommended for post-exposure prophylaxis (PEP) to prevent Lyme disease in areas of high incidence. However, it is not known how often or for which patients PEP is used. We aimed to describe recent patterns of single-dose doxycycline medication claims in states with high and low Lyme disease incidence, and the associated patient and prescription characteristics in a large national commercial insurance claims database.

Methods
Outpatient medication claims in the IBM Watson Health MarketScan Database®, a large nation-wide database of de-identified insurance claims filed between January 1, 2014–December 31, 2017 were reviewed. Claims of single-dose doxycycline were identified and associated patient demographics and medication characteristics were analyzed.

Results
During 2014–2017, 66,210 medication claims for single-dose doxycycline were filed by 63,112 enrollees; mean annual incidence of receiving at least one single-dose doxycycline prescription was 56 per 100,000 enrollees. Mean patient age was 43 years (IQR 33–56 years); only 8% were for children aged <18 years. About half (46%) were male patients. Most claims (71%) were made by patients residing in the 14 states with high Lyme disease incidence, defined as an average annual incidence of ≥ 10 confirmed Lyme disease cases per 100,000 population. The majority (80%) of medication claims were during the 6 months of peak tick activity (April–July for nymphal ticks and October–November for adult ticks).

Conclusion
Single-dose doxycycline medication claims are common in states with high Lyme disease incidence and are highest during months of peak tick activity, consistent with the assumption that most single-dose doxycycline is used for Lyme disease PEP. Use of single-dose doxycycline to prevent Lyme disease is infrequent in children, despite being a group at high risk for Lyme disease. Efforts to educate pediatric healthcare providers and parents should be made to increase Lyme disease PEP access for children.

Disclosures
All authors: No reported disclosures.
1615. Influenza Outbreaks in Long-Term Care Facilities, 2017–2018 Influenza Season, Dallas, Texas
Authors: Chung Wendy , Shim Kyoo , Jung David , Blackwell James , Richardson Folasuyi , Schmalstieg Aurelia 
Published: October 2019

Abstract

Background
High rates of influenza-related hospitalizations and deaths occurred in the United States during the 2017–2018 influenza season. A record number of influenza outbreaks were reported in long-term care facilities (LTCF) in Dallas County. Public health surveillance of influenza-related intensive care unit (ICU) admissions and deaths in acute care hospitals improved early identification of outbreaks in LTCFs.

Methods
A confirmed LTCF influenza outbreak was defined as at least 1 lab-confirmed influenza case plus at least 1 case of influenza-like illness among residents or staff within 72 hours. Outbreaks were self-reported by facilities or identified by the health department during investigations of ICU hospitalizations and deaths. CDC guidance for influenza outbreak management was provided and daily active surveillance was continued for at least 1 week after the last case was identified. Data collected included: numbers of ill residents and staff, vaccination rates, dates of illness and chemoprophylaxis initiation, hospitalizations and deaths. Fisher exact tests and Chi-square were performed using SAS 9.4.

Results
During this influenza season, 32 confirmed influenza outbreaks were identified in Dallas County LTCFs: 17 in skilled nursing facilities (SNF), 13 in assisted-living facilities (ALF) and 2 in hybrid SNF/ALF. The average attack rate in residents was 9.8% (range: 1–35%). Influenza hospitalization rates were higher in ALF compared with SNF outbreaks (OR: 2.2). Influenza-associated mortality rates were higher in ALF compared with SNF (OR: 3.1). Of the 32 outbreaks, 20 (63%) were self-reported by facilities to public health and 12 (38%) were identified through health department review of influenza-associated ICU hospitalizations. Facilities where outbreak cases were identified through public health surveillance of ICU admissions had significantly lower overall attack rates (5.9% vs. 12.1%, P = 0.01) and shorter time to initiation of facility-wide chemoprophylaxis (0.4 vs. 2.4 days, P = 0.05).

Conclusion
Active surveillance of influenza-associated ICU admissions in acute-care hospitals facilitated the early identification of influenza outbreaks in LTCFs, which was associated with lower overall attack rates and shorter time to initiation of facility-wide chemoprophylaxis.

Disclosures
All authors: No reported disclosures.
1634. A Mobile Application for Management and Surveillance of Vector-borne Diseases in Cali, Colombia: An Evaluation of Usability and Acceptability in a Hospital Setting
Authors: Rodriguez Sarita , Sanz Ana M , Llano Gonzalo , Navarro Andres , Parra-Lara Luis Gabriel , Krystosik Amy , Rosso Fernando 
Published: October 2019

Abstract

Background
Vector-borne diseases are a public health problem in Colombia, an area that has become hyperendemic for dengue virus. This situation has been aggravated by the introduction of other arboviruses such as chikungunya and Zika in the last 3 years. Mobile health (mHealth) offers new strategies for strengthening healthcare and surveillance systems. A large number of mHealth tools are available; however, very few have been evaluated regarding usability and acceptability. This study aimed to evaluate the usability and acceptability of a mobile application, FeverDX, as a support tool in the management of patients with febrile syndrome and suspected vector-borne infection by general practitioners from Colombia.

Methods
The usability and acceptability of FeverDX were evaluated using the modified version of the Mobile Application Rating Scale (uMARS). The evaluation included aspects of content, user engagement, functionality, user-interface design, impact, and subjective quality.

Results
Between December 2016 and January 2017, a total of 20 general practitioners evaluated FeverDX. Seventy-five percent of the evaluators reported being aware of the Colombian Ministry of Health guidelines for diagnosis and management of arboviruses. 80% of evaluators partially or completely agreed the application information agreed with management guidelines. On uMARS scale, FeverDX excelled regarding impact (median = 5/5, IQR = 5–5); functionality (5/5, 4.8–5); and information and scientific basis (4/5, 4-4). FeverDX scored well regarding user feedback (median = 4/5, IQR = 4–4.5); design and esthetics (4/5, 4–4.3); and subjective assessment of quality (4.5/5, 4.3–4.8).

Conclusion
Despite a large number of mHealth tools available, the literature lacks evaluated and evidence-based mobile technology. Applying Information and Communications Technologies in health areas can strengthen care processes and facilitate the detection and reporting of reportable surveillance diseases. Assess the usability and acceptability of mobile health applications increases the reliability of these technologies. The mobile app, FeverDx, can improve adherence to guidelines for management and prevention of prevalent diseases.

Disclosures
All authors: No reported disclosures.
1640. Pertussis Testing in the Department of Veterans Affairs, 2010–2018
Authors: Schirmer Patricia , Oda Gina , Lucero-Obusan Cynthia , Holodniy Mark 
Published: October 2019

Abstract

Background
Bordetella pertussis causes a highly contagious, nationally reportable respiratory illness resulting in violent coughing. Pertussis outbreaks continue despite an available vaccine. Appropriate pertussis testing depends on timing from the onset of symptoms. Culture testing within 2 weeks from symptom onset is gold standard, while PCR testing is reasonable up to 3–4 weeks and serology testing 2–12 weeks from symptom onset per CDC. We describe pertussis testing in the Department of Veterans Affairs (VA) from 2010–2018.

Methods
VA data sources were queried for all Bordetella pertussis tests (culture, DFA, IgA, IgG, IgM, and PCR) from January 2010 to December 2018. Data were compared across years. A random selection of 10 patient charts with both positive and negative test results for each type of testing were reviewed to determine timing from onset of symptoms to testing.

Results
From 2010 to 2018, 37,356 pertussis tests (28,174 unique patients) were performed in VA nationally. Increased testing occurred in 2012 (most recent peak year) and PCR testing increased in 2014 with introduction of multiplex panels. Otherwise testing was stable between years (Figure 1). Positive test results included culture 1/252 (0.4%), DFA 4/204 (2%), IgA 459/1,546 (29.7%), IgM 168/1,189 (14.1%), IgG 1,156/2,291 (50.4%), and PCR 47/31,847 (0.2%) (Figure 2). Total positive tests per year ranged from 161 in 2015 to 313 in 2012. Across the years, IgG was the most common positive test. In 37/60 (62%) charts reviewed, appropriate test was chosen based on duration of symptoms. 9/60 (15%) had no symptom duration documented and 14/60 (23%) did not have appropriate pertussis testing chosen based on symptom duration. DFA testing chart reviews were not included as there is no CDC recommendation for DFA testing in pertussis diagnosis.

Conclusion
Number of pertussis-positive results remained stable despite increased testing, primarily from multiplex PCR testing. IgG, often a marker of immunity, was the most common test to be positive across the studied timeframe. In a small sampling of patients, about two-thirds received appropriate testing based on symptom duration. With the multitude of pertussis tests ordered, further education of clinicians on appropriate testing based on timing of symptoms is needed.

Disclosures
All authors: No reported disclosures.