bluuebunny/crossref_metadata_2025 huggingface dataset:
1536. Population Pharmacokinetic Analysis of Baloxavir Morboxil, a Cap-Dependent Endonuclease Inhibitor, in Adult and Adolescent Healthy Subjects and Influenza Patients and Exposure-Response Relationships in the Patients at High-Risk of Influenza Complications
Authors: Koshimichi Hiroki , Retout Sylvie , Cosson Valérie F , De Buck Stefan , Tsuda Yoshiyuki , Ishibashi Toru , Wajima Toshihiro
Published: October 2019

Background

Baloxavir marboxil is a prodrug of baloxavir acid which is a selective inhibitor of cap-dependent endonuclease. The global Phase 3 study conducted in the influenza patients at high-risk of influenza complications (CAPSTONE-2) enrolled adult and adolescent patients from 2016 to 2018. Baloxavir marboxil demonstrated significantly shorter time to improvement of influenza symptoms (TTIIS) than placebo. The aim of this study was to build a population pharmacokinetic (PK) model of baloxavir acid and to evaluate the exposure-response relationships in high-risk patients.

Methods

The population PK analysis was conducted on the pooled data from 13 clinical studies: 10 phase 1 studies, a phase 2 study, and 2 phase 3 studies. A total of 11846 plasma concentrations from 1827 subjects were used for this analysis. The influence of background characteristics including risk factors of influenza complications was assessed on the PK of baloxavir acid. The individual Cmax and AUC were estimated with an empirical Bayesian approach. Exposure-response analysis was conducted for TTIIS and virus titer in the high-risk patients.

Results

A 3-compartment model with first-order absorption and lag time was selected as a structural PK model, and well described the plasma concentrations. The population PK analysis suggested that (1) AUC in non-Asians was 30.7% lower than that in Asians, (2) body weight significantly affected the exposures to baloxavir acid, (3) the exposures in high-risk patients were similar to those in otherwise healthy patients, and (4) no PK differences were identified regarding the risk factors for influenza complications. The exposure-response analyses showed that the body weight-based dose regimen (40 mg for the patients weighing <80 kg and 80 mg for the patients weighing ≥80 kg) shortened TTIIS and reduced virus titer for both type A and B influenza, across the entire range of baloxavir acid exposures observed in CAPSTONE-2 although subject number in the lowest exposure group was limited and it was difficult to discuss the magnitude of the responses accurately.

Conclusion

The results of the population PK analysis and exposure-response analyses provide useful information for understanding the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil.

Disclosures

All authors: No reported disclosures.
1546. Efficacy of Daptomycin Combinations Against Daptomycin-Resistant Enterococcus faecium Differs by β-lactam
Authors: Kebriaei Razieh , Stamper Kyle , Rice Seth , Maassen Philip , Singh Kavindra V , Dinh An Q , Rios Rafael , Diaz Lorena , Murray Barbara E , Khan Ayesha , Tran Truc T , Arias Cesar A , Rybak Michael J
Published: October 2019

Background

We have previously demonstrated that daptomycin (DAP) combinations with β-lactams offer enhanced bactericidal activity and prevent the emergence of resistance in Enterococcus faecium infections. Although the mechanisms of DAP resistance in enterococci are not fully comprehended, they are associated with alterations in cell envelope phospholipids assembly which leads to either repulsion of the drug from cell exterior or diversion from the cell septum. In this context, we sought to evaluate combinations of DAP with a panel of β-lactams including ampicillin (AMP), amoxicillin (AMX), ceftaroline (CPT), ceftriaxone (CRO) and ertapenem (ERT).

Methods

E. faecium R497 harboring liaSFR mutations (DAP MIC of 16 mg/L) was evaluated in a simulated endocardial vegetation (SEV) pharmacokinetic and pharmacodynamic model over 336 h at a starting inoculum of 109 log10 CFU/g. DAP 10 mg/kg/day combinations with AMP, AMX (2 g continuous infusion), CPT 600 mg q 12 h, CRO 2g q 24 h or ERT 1 g q 24 h were evaluated. The emergence of DAP resistance was determined daily over the course of treatment.

Results

DAP alone was not bactericidal and high-level DAP resistance was observed (MIC increase from 16 to 64 µg/mL). Combination of DAP+AMP offered a significant reduction in log10CFU/g amounts (Up to 7 log10 CFU/g and to detection limits) in 24h in with no emergence of DAP resistance. DAP 10+ AMX caused 6–6.5 log10 CFU/g reduction and counts were maintained around the detection limit while demonstrating no increased resistance. Dose de-escalation with AMP indicated that even DAP 4 mg/kg/d with AMP (2g) combination, reached detection limit at 168 h with no further resistance. None of the CPT, CRO or ERT regimens in combination with DAP was effective against R497 and elevated DAP MICs (>64 µg/mL) was observed during the 14-day model.

Conclusion

Combination of DAP+AMP offered the most encouraging results against E. faecium R497, while DAP+AMX caused enhanced reduction. The reason for this discrepancy in various β-lactam activity may be related to diverse β-lactam targeting or affinity toward PBP proteins. Further dissection of our observations is warranted to understand the optimized DAP-β-lactam combination and consequently improve patient outcomes and prevention of resistance.

Disclosures

All authors: No reported disclosures.
1554. Nebulized Liposomal Amphotericin B for Treatment of Murine Pulmonary Mucormycosis
Authors: Sandoval Adilene , Adler-Moore Jill
Published: October 2019

Background

Pulmonary mucormycosis, a life-threatening infection of immunocompromised individuals, can have a 95% mortality rate, even with treatment. Intravenous (IV) liposomal amphotericin B (AmBisomeâ, AmBi) is used to treat the infection, but rapid growth of the pathogen can limit the drug’s effectiveness. In the present study we investigated whether nebulized (nebz) AmBi could improve treatment outcome using a neutropenic murine model of pulmonary mucormycosis.

Methods

Rhizopus oryzae (ATCC MYA4621) was grown on Potato Dextrose Agar for 3–7 days, followed by spore harvesting, and determination of spore viability. Male ICR mice were immunosuppressed with 200 mg/kg of cyclophosphamide d-2, d0, d+2, d+4, and d0 challenged intranasally with 1 × 106 spores. In Study 1, mice (n = 16 mice/gp) were given AmBi at 7.5 or 10 mg/kg IV for 6 days, or nebz AmBi for 20 minutes (1.33 mg/mL AmBi in reservoir) for 4 days. In Study 2, 16 mice/gp were given AmBi at 15 mg/kg IV for 6 days or nebz AmBi for 7 days. PBS was the control. Lungs and kidneys were collected d+6 to determine drug concentration by a bioassay (n = 7–8 mice/gp) and morbidity (n = 8 mice/gp) monitored to d+21.

Results

In Study 1, survival was significantly better with nebz AmBi for 4 days (50%) or 10 mg/kg IV AmBi (33%) vs. 7.5 mg/kg IV AmBi (0%) (P < 0.003). In Study 2 with 13% survival in the PBS mice, 7 days of nebz AmBi produced 100% survival and 15 mg/kg IV AmBi gave 83% survival (P < 0.02 vs. PBS), underscoring the need for more intensive treatments. In Study 2, we also observed that average lung drug levels with nebz AmBi were significantly lower (3 μg/g lung) than with 15mg/kg AmBi IV (19 μg/g lung) (P = 0.003), even though both treatments were comparably effective. Kidney drug levels with 15 mg/kg AmBi IV were 13 μg/g and in comparison, nebz AmBi produced no detectable drug.

Conclusion

Daily nebulization of AmBi for one week or a high dose of IV AmBi at 15 mg/kg for 6 days protected the mice from severe pulmonary mucormycosis caused by R. oryzae, delivering effective drug levels to the lungs. The IV treatment yielded elevated levels of drug in the kidneys, while nebulization with AmBi produced no detectable drug in the kidneys. This indicated that nebz AmBi would be a less nephrotoxic, but still very effective route for drug delivery.

Disclosures

All authors: No reported disclosures.
1555. Risk of Developing Acute Kidney Injury in Patients Receiving Piperacillin–Tazobactam and Vancomycin Compared with Those on Piperacillin–Tazobactam and Telavancin
Authors: Reilly Joseph , Nhan Ethan , Erb Rebecca , Whittaker Cristen A , Trivedi Manish
Published: October 2019

Background

The combination of piperacillin–tazobactam (PIP-TAZO) and vancomycin is associated with an increased frequency of acute kidney injury (AKI) in patients when compared with either agent alone. Like vancomycin, telavancin is also used for gram-positive infections and has been reported to cause AKI, but there is a paucity of data regarding the development of AKI with the combination of PIP-TAZO and telavancin. The purpose of this study was to compare the incidence of AKI in patients receiving PIP-TAZO with concomitant vancomycin or telavancin.

Methods

This retrospective cohort study included patients admitted between November 2016 and March 2019 who received at least 2 days of either vancomycin or telavancin in combination with PIP-TAZO. Patients were excluded if they had a baseline calculated creatinine clearance of less than 20 milliliters per minute or were receiving renal replacement therapy. Any cases of AKI were defined as a serum creatinine increase of 0.3 milligrams per deciliter (mg/dL) or an increase in creatinine of 1.5 times baseline when observed within 7 days of the studied antibiotic combinations. Statistical analysis was performed to compare baseline characteristics and the development of AKI between the two groups.

Results

Ninety-four patients with an average age of 55 years met the inclusion criteria. Forty-seven patients were included in both treatment arms. There were no statistically significant differences observed between study group baseline characteristics. All patients received PIP-TAZO 3.375 grams every 8 hours as a 4-hour infusion and the average telavancin dose was 7.5 mg/kg. Seventeen of 94 (18%) patients developed AKI, 8(17%) in the vancomycin and PIP-TAZO group and 9 (19%) in the telavancin and PIP-TAZO group (P = 1.0). No patients required dialysis.

Conclusion

The development of AKI appears to be similar when comparing vancomycin and PIP-TAZO to telavancin and PIP-TAZO in our population. It is noteworthy that PIP-TAZO was given as an extended infusion and telavancin dosing was lower than the manufacturer recommendations in this evaluation. Additional studies are warranted to further examine the occurrence of AKI with these antibiotic combinations.

Disclosures

All authors: No reported disclosures.
1560. Pharmacokinetics–Pharmacodynamics (PK-PD) of Gepotidacin (GEP) Against Escherichia coli in Murine Pyelonephritis and Thigh Infection Models
Authors: Barth Aline , Mininger Cindy l , Lewandowski Thomas , Hossain Mohammad , Rittenhouse Stephen , Hoover Jennifer
Published: October 2019

Background

GEP, a first in class novel triazaacenaphthylene bacterial topoisomerase inhibitor, inhibits bacterial replication and has in vitro activity against key pathogens implicated in a range of infections, including drug-resistant strains of E. coli associated with acute cystitis.

Methods

PK and PD studies were conducted in murine (male CD-1 mice) thigh and kidney infections. The administered doses ranged from 1 to 200 mg/kg SC every 6 hours starting 1-hour post-infection. Infected tissues were evaluated for bacterial burden at 24-h post-infection (baseline controls at 1-hour post-infection). Plasma and tissue samples (kidney or thigh homogenates) were collected at 15, 30, 60, 120, 240 and 360 minutes. A population PK (PopPK) model was built in NONMEM using plasma exposures. Efficacy was determined against E. coli ALL, 997577, ATCC25922, IR5 and NCTC13441 (MICs of 1 to 4 µg/mL) in thigh-infected neutropenic (I-) mice and against E. coli ALL in kidney-infected immunocompetent (I+) and I- mice. The PopPK model was used to determine GEP exposures associated with efficacy. PK-PD analyses were conducted using Phoenix WinNonLin 6.3 (Pharsight). The change in log10 colony-forming units (CFU) from baseline were correlated with free drug (f) AUC:MIC using an inhibitory model from the Phoenix library, and model parameter values for each isolate were used to calculate the plasma fAUC:MIC associated with stasis, 1- or 2-log10 reductions in CFU.

Results

Plasma PK data were best fit by a 1-compartment IV model with first-order elimination and were similar in I+ vs. I- and thigh- vs. kidney-infected mice. The AUC0-6 of GEP in kidney was approximately 4- to 5-fold higher than in plasma while the AUC0-6 in thigh was approximately half of plasma. In the I- thigh model, median plasma fAUC:MIC ratios for stasis, 1- or 2-log10 reductions in CFU were 11, 16, and 25 (ranges 3–17, 4–25 and 7–40), respectively. Efficacy vs. E. coli ALL was similar in I- mice infected in thigh or kidney. In I+ mice, the PK-PD target was reduced by half.

Conclusion

Median plasma fAUC:MIC targets ranged from 11 to 25. Higher drug levels in kidney vs. plasma or thigh did not translate into improved efficacy in pyelonephritis vs. thigh-infection models.

Disclosures

All authors: No reported disclosures.
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

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

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

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

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

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

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

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

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

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.
1650. Knowledge and Attitudes Toward Influenza Vaccination Among Hispanics: A Survey Conducted in Latin American Consulates in South Florida
Authors: Soler Hidalgo Maria L , Abbamonte John M , Regalini Laura , Schlesinger Mariana , Alcaide Maria L , Dickinson Gordon M
Published: October 2019

Background

Each year Influenza causes between 12,000 and 56,000 deaths, and over half a million of hospitalizations in the United States. Despite the widespread availability of vaccination, immunization coverage is low. Less than half of American adults receive the influenza vaccine, and there is a disparity between Hispanic and non-Hispanics, with only 35.9% of Hispanic compared with 45.9% of white non-Hispanics receiving the vaccine. In Miami, South Florida, over two-thirds of the population is Hispanic, and rates of influenza vaccination are low. This study aims to identify the knowledge and attitudes toward influenza vaccination among members of the adult Hispanic community in Miami, and to identify barriers to vaccination in this population.

Methods

This is a cross-sectional study conducted during the influenza season in 2017 and 2019 (October to December). A survey was administered in the waiting rooms of participating Latin American Consulates (Argentina, Colombia, Ecuador, Guatemala, Honduras, Mexico, Peru, and Uruguay) in Miami. Participants included were older than 18 years, Hispanic, and with residence in the United States for more than 6 months. The participants accepted the inform consent orally. The survey was voluntary and anonymous.

Results

We enrolled 970 adults. The median age was 43 years, 50% were male, 60% had health insurance, and 67% had completed education of high school or higher. Knowledge regarding influenza and vaccination was low (78% believed asymptomatic individuals could transmit influenza, 14% knew that vaccination is recommended during the winter months, 50% felt not everyone should be vaccinated, 25% believed the vaccine causes influenza, and 7% autism). About one quarter (27%) received the influenza vaccine annually, 35% sometimes, and 38% never. Using multinomial logistic regression, we identified age χ2(2) = 19.38, P < 0.001, consulate χ2(6) = 160.21, P < 0.001, and insurance status χ2(2) = 23.04, P < 0.001 as predictors of receiving vaccination. Neither gender, nor education level found to be associated with vaccination behavior.

Conclusion

Immunization rates in the adult Hispanic population are low. Interventions to improve vaccination among Hispanics who are older and lack of health insurance are urgently needed in the diverse Hispanic community.

Disclosures

All authors: No reported disclosures.
1652. Equivalent HIV Outcomes for Persons with HIV after Re-engagement in HIV Care with Prior or New Provider
Authors: Udeagu Chi-Chi N , Shah Sharmila , Braunstein Sarah
Published: October 2019

Background

New York City (NYC) health department staff assist people with HIV (PWH) deemed out of care (OOC) per NYC HIV Surveillance Registry to re-engage in HIV care with their last known treating provider/parent clinic or, if preferable/necessary (e.g., moved to a new neighborhood), a new NYC provider. We examined retention in care and viral suppression (VS) of PWH re-engaged in care in a group who agreed to return to care and were cared for by either their previous or a new provider.

Methods

We analyzed data from 2009 to 2015 on PWH who had ≥2 CD4 count or viral load (VL) test reports in the NYC HIV Registry who fell out of care and then re-engaged in care. We compared characteristics, timeliness and retention in care (≥2 CD4 or VL, ≥90 days apart) and VS (last VL ≤200 copies/mL) of PWH overall and also according to whether they returned to their last known vs. a new provider in year 2 post re-engagement in care.

Results

From 2009–2015, 882 persons were re-engaged in care by the health department. Most were diagnosed 5–10 (27%) or >10 (67%) years prior, and were OOC for 1–3 years (70%) or >3 years (20%). Most re-engaged PWH were male (63%), black (56%) or Hispanic (34%), US-born (79%), aged 30–49 (48%) or ≥50 (40%) years. Risk factors for HIV included heterosexual transmission (39%), male-sex-with-male (26%) or injection drug use (18%). Twenty-two percent had history of homelessness and 5% incarceration. Fifty-one percent and 49% re-engaged in care with their prior or a new provider, respectively. PWH re-engaged with prior providers vs. new providers had lower rates of prior or current homelessness (17% vs. 28%, P = 0.0001), PWH re-engaged to prior vs. new providers had their first lab reports and achieved VS earlier (1 vs. 2 months, and 4 vs. 5 months, respectively (both P < 0.05). Proportions of PWH re-engaged to prior or new providers and retained in care (92% vs. 91%, respectively) or with VS (73% vs. 75%, respectively) in year 2 did not differ.

Conclusion

Our results show that health department efforts to re-engage previously OOC-PWH in HIV care resulted in more than 70% achieving VS. Assignment to a new provider resulted in earlier VS but did not affect 2-year VS or care retention. PWH who re-engage in care can safely be given the choice between known or new providers.

Disclosures

All authors: No reported disclosures.
1659. Electronic Consultations Combined with a Video Supported Powerpoint-based Pre-Travel Education Is Equivalent to In-Clinic Face-to-Face Pre-Travel Consultations in Appropriately Selected Travelers
Authors: Kasten Mary J , Virk Abinash , Mandrekar Jayawant , Springer Donna J
Published: October 2019

Background

Pre-travel consultation involves an in-clinic face-to-face consult (F2F) with a Travel Medicine provider. F2F involves education/counseling which is time-consuming for both patients and providers. Although electronic consultations (synchronous and asynchronous) are well established in many subspecialties, pretravel eConsults are not well known. We compared pretravel education via F2F to an innovative hybrid electronic consultation (HeC) combined with a Video Supported PowerPoint (VSP) for selected travelers.

Methods

We conducted a prospective trial comparing HeC-VSP to F2F to determine the quality of pretravel education. Study was approved by the Mayo Clinic IRB. Patients were enrolled from May 2014 through May 2015. Patients in both arms were given pretravel and post-travel surveys. Exclusions included age less than 18 years, first trip to Africa, immunocompromised host, non-English-speaking traveler, or travel for longer than 4 weeks.

Results

194 patients were enrolled; 100 in HeC-VSP and 94 in F2F arm completed pretravel survey. Post-travel survey was completed in 54.2% (51/94) of the F2F, 67% (67/100) in the HeC-VSP group. The groups are similar in demographics and prior travel experience (Table 1). 36.2% of the F2F group felt that the consultation could have been effectively accomplished through a video-based education, while 33% felt that a F2F was needed; in contrast a majority (63.3%) in the HeC-VSP group would not have preferred a F2F consultation. HeC-VSP-based pretravel education was similar compared with that provided via the F2F consults. There were no statistically significant differences in the responses obtained in both groups to knowledge assessment questions (Table 2) except for one question. A higher proportion (76/100; 76%) in the HeC-VSP group compared with 55.4% (51/94) chose the correct response (P = 0.0018) regarding management of bloody diarrhea with fever. Self-reported change in behaviors to prevent travel-related illnesses was reported overall in 53% of the patients with no statistically significant differences between the groups.

Conclusion

Nonsynchronous eConsultation combined with VSP provides a viable solution to provide pretravel education for a select travel population.

Disclosures

All authors: No reported disclosures.
1660. Protective Effect of Living with Animals on Diarrheal Illness Among Children Younger Than Five in Sub-Saharan Africa and South Asia
Authors: Murray Meghan T , Neu Natalie , Neu Natalie , Larson Elaine
Published: October 2019

Background

Diarrheal disease is one of the top three causes of death in children <5 years old, with the majority occurring in sub-Saharan Africa and South Asia. Animals are known reservoirs of diarrheal pathogens. While previous studies have investigated companion animals and livestock as contributors to human diarrheal disease, few have investigated this association in sub-Saharan Africa and/or South Asia among children younger than 5 years old. The aim of this study was to determine the relationship between animals living in or near the home and diarrheal disease in this population.

Methods

We conducted a secondary analysis of the Global Enteric Multicenter Study (GEMS), a case–control study that described the epidemiology of and evaluated the risk factors for diarrheal illness in children <5 years old living in sub-Saharan Africa and South Asia. Children with moderate-to-severe diarrhea (MSD) were matched to community controls without diarrhea. Associations between the predictor of animals present in a child’s living environment and the outcomes of diarrhea and diarrheal pathogens were assessed using multivariable conditional logistic regression with alpha = 0.05. Known risk factors for MSD were assessed for confounding.

Results

From December 1, 2007 to March 3, 2011, there were 9,439 cases with MSD and 13,128 controls enrolled in GEMS. 87% of children had at least 1 animal present at their home. When controlling for exclusive breastfeeding, access to an improved water source, access to a private improved sanitation facility, and the number of children <5 living in the home, children were less likely to have MSD if there was at least one animal present at their home (aOR 0.66, CI95 0.59 – 0.74). Children living with an animal were also 15% less likely to be colonized or infected with a viral diarrheal pathogen (aOR 0.85, CI95 0.72–0.99), when controlling for exclusive breastfeeding. There were no significant differences in the presence of bacterial or protozoal pathogens in the stool of children with and without animals present at their home.

Conclusion

In contrast to prior research, having an animal present at the home does not appear to increase the risk of childhood diarrhea. Furthermore, the presence of animals may have a protective effect against viral diarrheal disease in young children. Additional research is needed to gain greater understanding of this relationship.

Disclosures

All authors: No reported disclosures.