bluuebunny/crossref_metadata_2025_split huggingface dataset:
1557. Population Pharmacokinetics of Suvratoxumab (MEDI4893), an Extended Half-life Staphylococcus aureus Alpha Toxin-Neutralizing Human Monoclonal Antibody, in Healthy Adults and Patients on Mechanical Ventilation in Intensive Care Units
Authors: Pierre Vadryn , Francois Bruno , Hernandez-Illas Martha , Sánchez Garcia Miguel , Wu Yuling , Eggimann Philippe , Laterre Pierre-Francois , Huberlant Vincent , Viña Lucia , Boulain Thierry , Ruzin Alexey , Bretonnière Cédric , Pugin Jerome , Trenado Álvarez José , Bellamy Terramika , Shoemaker Kathryn , Ali Omar , Lee Nancy , Dequin Pierre-Francois , Jafri Hasan S , Roskos Lorin , Colbert Susan , Khan Anis 
Published: October 2019

Abstract

Background
Suvratoxumab (suvra), an extended half-life (~80 days), Staphylococcus aureus (SA) alpha toxin-neutralizing IgG monoclonal antibody, is under investigation for prevention of SA pneumonia in patients on mechanical ventilation (MV). We characterized the serum PK of suvra using population pharmacokinetics (popPK) in both healthy volunteers and MV patients and quantified the proportion of patients reaching the serum target of 211 μg/mL at 30 days post-dose.

Methods
The popPK analysis included 1,368 serum samples from two early phase studies (NCT02296320; EudraCT 2014-001097-34): (1) Phase 1 study in 26 healthy adults receiving single IV suvra doses ranging from 0.225g to 5g, with PK sampled up to 360 days; and (2) Phase 2 study in MV patients with PCR-confirmed SA colonization of lower respiratory tract receiving one suvra IV dose of 2g (n = 15) or 5g (n = 96), with PK sampled up to 100 days.

Results
A two-compartment linear model with weight-based scaling of the PK parameters adequately described the serum PK data (Figure 1). MV status, number of days on MV, and age impacted the PK of suvra. A moderate between-subject variability (<45% CV) was estimated for key PK parameters. An estimated two-fold increase in MV patients’ volume of distribution parameters compared with healthy volunteers explained the observed Cmax differences between the two groups (1145±369 μg/mL vs. 1783±396 μg/mL) (Figures 2 and 3). Although age, MV status and days on MV post-dose appeared to be associated with higher systemic clearance (CL) in the model, this estimate could be biased due to limited PK data available for only one half-life (~90 days) of the drug in MV patients (Figure 2). More patients achieved suvra levels above the PK target following the 5 g (73.5%; 50/68) vs. 2 g dose (7.6%; 1/13) at 30 days post-dose.

Conclusion
MV status, post-dose duration on MV, body weight, and age were identified as statistically significant covariates influencing the PK of suvra. Serum PK and popPK analyses support the 5g dose for future studies with suvra in MV patients.

Disclosures
All authors: No reported disclosures.
1562. Safety and Efficacy of High-Dose Cefazolin Therapy in Obesity
Authors: Simpson Timothy , Shah Sneha , Pogue Jason M , Wu Janet 
Published: October 2019

Abstract

Background
Obesity leads to altered pharmacokinetics through changes in volume of distribution and clearance, which can impact antimicrobial dosing. Although there is data to support higher cefazolin pre-operative dosing for surgical prophylaxis, data evaluating treatment doses of cefazolin in obese patients is lacking. This study was designed to assess the safety and efficacy of high-dose (HD) cefazolin compared with traditional-dose (TD) cefazolin in obesity.

Methods
This was a multicenter, retrospective, cohort study of patients admitted from September 1, 2013 to August 31, 2018. Obese adults, defined as a BMI > 30 kg/m2, receiving cefazolin for at least 48 hours for bacteremia or skin and soft-tissue infection were eligible for inclusion. Patients with creatinine clearances <30 mL/minute or positive MRSA cultures were excluded. TD cefazolin was defined as 1–2 g IV every 8 hours and HD cefazolin was defined as 2 g every 4–6 hours. Patients were matched 1:1 based on indication, severity of illness, and BMI. Primary objective was to compare rates of treatment-emergent adverse events (TEAE). Secondary outcomes included comparison of treatment failure rates and 30-day readmission.

Results
A total of 332 patients (166 matched pairs) were included in this analysis. Baseline demographics were similar between groups with the exception of higher age in the TD group (61.8 TD vs 55.1 HD; P < 0.001) and more males in the HD group (39.2% TD vs. 65.6% HD; P < 0.001). Median Charlson comorbidity index was also higher in the TD group [4 (2–6) TD vs. 3 (1–4) HD; P < 0.001]. There were no differences in TEAE between groups (24.1% TD vs. 16.9% HD; P = 0.103). Treatment failure occurred more frequently in the TD group (24.7% TD vs. 15.1% HD; P = 0.028), driven primarily by rates of readmission secondary to recurrence or relapse of the index infection (18.7% vs. 11.5%; P = 0.07).

Conclusion
There were no differences in TEAE in patients who received TD cefazolin vs. HD cefazolin therapy. Obese patients receiving TD therapy experienced higher treatment failure than those receiving HD therapy. Dose-optimization strategies with cefazolin in obese patients should be further explored.

Disclosures
All authors: No reported disclosures.
1564. Target Attainment of Empiric Vancomycin Therapy to Achieve Safe and Effective Exposure When it Matters Most: How Much of the Drug Do We Really Need in the First 48 Hours?
Authors: Yassin Arsheena , Chin Titania , Meleshkina Daria , Ghanbar Mohammad , Sassine Joseph , Olivo Freites Christian , Stavropoulos Christine , Farkas Andras 
Published: October 2019

Abstract

Background
Empiric dosing of vancomycin (VAN) to reach targets is a daunting task due to the large variability observed in the pharmacokinetics of this agent. With the change to AUC driven dosing on the horizon, the goal of this study was to establish empiric dosing requirements of vancomycin that effectively achieve the desired AUC of 400 to 600 mg hours/L targets in the first 48 hours of therapy.

Methods
VAN TDM data were used in this analysis. A two-compartment model was fitted with Bayesian routines to establish the AUCs. Then, the AUC achieved was used to identify the desired total daily dose (TDD, capped at 4,500 mg) needed to attain an AUC in the target range for days 1 and 2, per patient. Next, multivariable regression was undertaken to predict this desired dose with frequently calculated weight and renal function indices. Last, model validation in a test data set based on calculated ME, RMSE and their 95% CI took place, and then the best model was used to simulate TDDs at 24 h intervals. To evaluate the agreement between the 2 pharmacists selecting the final TDDs by screening the simulated regimens, a weighted Kappa was calculated.

Results
1450 concentrations from 268 patients (60.9% male) with mean (IQR) age of 62.8 (52.7, 75) years, weight of 79.1 (63.2, 90.9) kg and CrCl of 76.7 (36.8, 110.6) mL/minute were analyzed. Fit of the model to data was excellent with R2 = 0.98 (Figure 1). AUC attainment with actual dose vs. the AUCs based on the desired dose was poor (Figure 2). Final regression model [ME (95% CI) 31.58 (−160.38, 217.34) mgs; RMSE (95% CI) 761.98 (628.19, 895.93) mgs] identified adjusted body weight (ABW) (P = 0.02), CrCl (P < 0.001), age (P = 0.05) and sex (P = 0.01) on day 1, vs. CrCl (P < 0.001), age (P = 0.02) and sex (P = 0.002) on day 2 as predictors of TDD. Kappas showed near perfect agreement for day 1 (0.992, P < 0.01) and day 2 (0.883, P < 0.01) between the raters resulting in the selection of the final dosing regimens (Figures 3 and 4).

Conclusion
Our model accurately identified the 4 major variables most likely to explain VAN variability in predicting AUC in the first 48 hours. These detailed dosing recommendations—strengthened by rigorous external validation and near perfect between rater agreements—allow for the design of safe and effective AUC driven empiric dosing regimens.

Disclosures
All authors: No reported disclosures.
1589. Ceftolozane–Tazobactam Activity Against Difficult-to-Treat Resistance in Pseudomonas aeruginosa from Bloodstream Infections in US Hospitals
Authors: Shortridge Dee , Ryan Arends S J , Duncan Leonard R , Streit Jennifer M , Flamm Robert K 
Published: October 2019

Abstract

Background
Infections caused by Pseudomonas aeruginosa (PSA) resistant to first-line agents are difficult to treat and require using more toxic antimicrobials, such as amikacin (AMK) and colistin (COL). Kadri et al. recently described the category of difficult-to-treat resistance (DTR) as intermediate or resistant to all tested first-line agents (fluoroquinolones, carbapenems, and extended-spectrum cephalosporins). Ceftolozane–tazobactam (C-T) is an antibacterial combination of an antipseudomonal cephalosporin and a β-lactamase inhibitor. C-T has been approved in &gt;60 countries to treat complicated urinary tract infections, acute pyelonephritis, and complicated intra-abdominal infections. The filing is in progress for treatment of hospital-acquired pneumonia, including ventilator-associated pneumonia. The Program to Assess Ceftolozane–Tazobactam Susceptibility (PACTS) monitors gram-negative (GN) isolates resistant to C-T worldwide. In this study, the activity of C-T and comparators against PSA bloodstream isolates that are DTR, multidrug-resistant (MDR), or extensively drug-resistant (XDR) were analyzed.

Methods
A total of 922 PSA isolates from BSI were collected between 2011 and 2018 from 35 PACTS hospitals in the United States. Isolates were tested for C-T susceptibility (S) by the CLSI broth microdilution method. Other antibiotics tested included cefepime (FEP), ceftazidime (CAZ), ciprofloxacin, levofloxacin (LEV), doripenem, imipenem, meropenem (MEM), piperacillin–tazobactam (PIP-TAZ), AMK and COL. Antibiotic-resistant phenotypes analyzed using CLSI (2019) breakpoints included MDR (nonsusceptible to ≥ 1 agent in ≥ 3 drug classes), XDR (susceptible to ≤ 1 agent in ≤ 2 drug classes), or DTR.

Results
The percent of DTR isolates was 4.8% when compared with 15.2% MDR and 9.3% XDR. The %S for C-T and other first- and second-line agents are shown in the table for each phenotype.

Conclusion
C-T demonstrated 97.1%S overall for BSI isolates, similar to AMK (97.8%) and COL (99.5%). C-T had better coverage than first-line drugs against MDR (81.4%) and XDR (72.1%), and 50% for the DTR isolates, which represented only 4.8% of isolates. Only AMK and COL had &gt; 75%S for DTR isolates.

Disclosures
All authors: No reported disclosures.
1596. Impact of Vancomycin Area Under Curve on Persistent Methicillin-Resistant Staphylococcus aureus (MRSA) Bloodstream Infections (BSI)
Authors: Alosaimy Sara , Jorgensen Sarah C J , Lagnf Abdulhamid , Zasowski Evan J , Trinh Trang D , Mynatt Ryan , Pogue Jason M , Rybak Michael J 
Published: October 2019

Abstract

Background
Persistent Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections (BSI) are associated with significant morbidity, mortality, and healthcare expenditures. Vancomycin (VAN) remains the treatment of choice for invasive MRSA BSI. Current guidelines for the treatment of MRSA BSI recommend a VAN AUC24h/MIC ratio ≥400. The Detroit Medical Center (DMC) implemented an AUC guided dosing strategy. However, data on the association between AUC24h and clinical outcomes in MRSA BSI are limited. We aimed to evaluate the association between VAN AUC24h and persistent bacteremia (PB) among patients with BSI.

Methods
Multi-center, retrospective cohort study from January 2015 to November 2018. We included adult patients with MRSA bacteremia treated with VAN for which AUC24h monitoring was performed. AUC was measured using 2-level guided dosing. The primary outcome was PB defined as continued positive cultures >72 hours after VAN initiation. Classification and Regression Tree (CART) analysis was performed to determine the AUC24h breakpoint (BP) most predictive of PB in the cohort. Mann–Whitney and Fischer exact tests were used for univariate analysis. The independent association between AUC24h, dichotomized at the CART-derived cut-point, was then examined through multivariable logistic regression analysis.

Results
Overall, 137 patients were included. The median age was 59 (18–85) years, 69.3% male, and 75.2% African American predominance. Most common sources of BSI were skin/soft tissue (39.4%), pneumonia (25.5%), and osteoarticular (16.8%). The median APACHE II score was 13 (8–20). Median time to microbiological clearance was 2.5 days (0.5–12). Patients with AUC24h ≤ 406.25 were more likely to have PB compared with those with AUC24h > 406.25 (59.4% and 35.2%, respectively; P = 0.002). After controlling for age, intensive care stay, and concomitant β-lactam therapy; AUC of ≤ 406.25 (aOR 2.767, 95% CI 1.212–6.318) and endocarditis (aOR 2.87, 95% CI 1.079–7.638) were independently associated with PB.

Conclusion
VAN AUC24h BP of <406.25 was independently associated with PB in patients with MRSA BSI. Our findings underscore the importance of VAN dose optimization to achieve timely bacterial clearance in MRSA bacteremia.

Disclosures
All authors: No reported disclosures.
1610. Implementation of Clinical Care Pathway Reduces Measles Exposures During Outbreak in New York
Authors: Daniel Jency , Patel Darshan , Sussner Rita M , Mack Lynda , Chen Donald S , Margaret. Nolan Sheila 
Published: October 2019

Abstract

Background
The United States is currently experiencing the largest measles outbreak since 1994. The New York outbreak started in October 2018 in several communities with low immunization rates for measles. Our institution is a referral center for the Hudson Valley and New York City. Failure to immediately recognize the disease early in the outbreak resulted in several exposure investigations and significant expenditure of time and resources. With evidence of ongoing transmission in local communities, we initiated a multi-pronged approach to recognize and limit potential measles exposures.

Methods
We developed a clinical pathway to alert Emergency Department (ED) staff and local Emergency Medical Service (EMS) agencies to the signs and symptoms of measles and provided steps for isolation, care, and testing for patients with possible measles. The ED staff and EMS personnel were educated in meetings and by posters, emails, and huddles. Reports of cases were made to infection control in real time, and local Departments of Health (DOH) were subsequently notified of suspected cases and exposures. We describe data pre and post-intervention. Chi-square was used to compare the number of patients requiring contact investigations for staff and patient exposures pre- and post-pathway implementation.

Results
From October 2018 through April 2019, 31 patients were evaluated for measles. Measles was diagnosed in 15 patients (1 adult, 14 children). Eight patients were admitted to the hospital, 3 required Pediatric ICU care. Pre-pathway implementation, 2 out of 9 (22%) evaluated patients resulted in exposure investigations; post implementation, 1 out of 22 (4.5%) evaluated patients required an exposure investigation (P = 0.18). The investigations conducted by our infection control department included 153 patients, 141 pre-implementation vs. 12 post-implementation. Nine patients required prophylaxis with immunoglobulin, and 10 patients received MMR vaccine as prophylaxis. No exposures resulted in clinical cases of measles.

Conclusion
Implementation of a clinical pathway to recognize and isolate suspected measles patients with ED staff and EMS personnel resulted in reduced exposures and improvement in communication with Infection Control and local DOH.

Disclosures
All authors: No reported disclosures.
1613. Rates of Hospitalization for Community-Acquired Pneumonia Among US Adults: A Systematic Review
Authors: McLaughlin John M , Khan Farid L , Thoburn Elizabeth A , Isturiz Raul E , Swerdlow David L 
Published: October 2019

Abstract

Background
Community-acquired pneumonia (CAP) develops in persons outside of a healthcare facility and is associated with significant morbidity and mortality. Estimating the incidence of CAP is challenging because it lacks a standardized case definition and because study designs and selection criteria vary. Reconciling these differences across studies is critical for understanding the true burden of CAP which, in turn, informs prevention strategies, including vaccination.

Methods
We performed a systemic literature review of studies describing the incidence of hospitalized CAP among adults in the United States. Specifically, we examined the impact of the following study characteristics on estimates of incidence: (i) study population, (ii) study type and data source, and (iii) diagnostic criteria for pneumonia.

Results
After review of 8361 articles as of January 31, 2019, we identified 26 studies which contained 39 unique CAP estimates. Among adults ≥65 years of age, annual rates of hospitalized CAP ranged from 847 to 3,500 per 100,000 persons with median = 1,830. Rates were lower in studies that excluded patients with healthcare-associated (but community-onset) pneumonia (HCAP; median = 2,003 vs. 1,286; P = .02) or immunocompromising conditions (median = 1,895 vs. 1,409; P = .29). Rates of CAP were also lower in studies that used more restrictive criteria for diagnosing pneumonia (e.g., pneumonia coded in any diagnosis position [median = 2,246] vs. pneumonia coded in the first position only [median = 1,375] in studies of administrative claims; P = 0.03). For adults <65 years of age, annual rates of CAP were lower (range = 89 to 1,024 per 100,000; median = 210).

Conclusion
CAP causes a significant disease burden among adults, particularly among those ≥65 years of age where the incidence of hospitalization is approximately 2,000 per 100,000 annually. Commonly-applied exclusion criteria (e.g., persons with HCAP or immunocompromising conditions) or restrictive case definitions (e.g., only including pneumonias coded in the primary diagnosis position) have led to systematic underestimation of CAP incidence in many previous studies. Understanding the true burden of adult CAP is critical for highlighting the ongoing need for expanded prevention programs, including vaccination.

Disclosures
All authors: No reported disclosures.
1617. Mumps in Detention Facilities that House Detained Migrants—United States, September 2018–April 2019
Authors: Leung Jessica , Elson Diana , Cloud Brandy , (Cody) McMurray Dakota , McNall Rebecca J , Hickman Carole J , Marlow Mariel 
Published: October 2019

Abstract

Background
Starting in September 2018, an unusually high number of mumps cases were reported in US adult detention facilities. Detention facilities usually involve close contact among detainees, facilitating transmission of mumps. Detainees in close contact with a mumps patient are at increased risk for acquiring mumps and should be offered a dose of MMR vaccine. We summarize the epidemiologic, clinical, and laboratory data for mumps cases in adult detention facilities during September 2018-April 2019.

Methods
Data were collected by health departments and US Immigration and Customs Enforcement (ICE) Health Services Corps and reported to CDC. Cases were classified according to the CSTE case definition for mumps and confirmed by RT-qPCR; molecular sequencing was performed on mumps-positive specimens.

Results
From September 2018-April 2019, 389 confirmed and probable mumps cases in adult migrants detained by ICE in 44 detention facilities were reported in 16 states (figure). The median age of patients was 24 years (range: 18–66); 94% were male. Vaccination status was unknown for all patients. Most (80%) patients were exposed while in custody of ICE or other US legal agency, 7% were exposed before apprehension, and custody status at exposure was unknown for 13%. Among 265 patients with data on complications, 15% had orchitis; at least 3 were hospitalized. Mumps genotype G, the most common genotype in US, was identified in specimens from 70 patients. This mumps response included >7,000 MMR vaccine doses distributed to affected facilities, and hundreds of exposed detainees placed under restricted movement in their facility each week. The response is ongoing as new cases continue to be reported.

Conclusion
This is the first report of mumps outbreaks occurring in multiple states and detention facilities during the same period. These outbreaks are costly and challenging to control. Identifying target groups for vaccination is challenging since detainees are frequently transferred and MMR vaccine does not prevent mumps in persons already exposed and infected. Effective public health interventions require an understanding of detention settings. Development of national guidance and resources for public health response to mumps and other infectious diseases in detention facilities would be beneficial.

Disclosures
All authors: No reported disclosures.
1619. Carbapenemase Producing Enterobacteriaceae in River Estuaries and Coastal Water of Netanya, Israel
Authors: Cohen Regev , Paikin Svetlana , Astrahan Peleg 
Published: October 2019

Abstract

Background
The role of the environment in the human epidemiology of carbapenem-resistant Enterobacteriaceae (CREs) is poorly understood. Several reports described carbapenemase-producing Enterobacteriaceae (CPE), cultivated from freshwaters of rivers and seawater, but there are no data from Israel. We encountered a young patient diagnosed as a rectal-carrier of 2 CPEs, both harboring the blaKPC sequence, after near-drowning in seawater near Netanya. In this study, we aimed to study river estuaries and the nearby Netanya beaches for the presence of CPEs.

Methods
On 2 occasions (June, July 2018) we filtered coastal water (Beit-Yanai and Sironit beaches) and freshwater (Alexander and Poleg estuaries) through 0.2µm sterile cellulose acetate membranes. Filtered bacteria were cultured in thioglycolyte broth media and transferred to different solid media. Enterobacteriaceae growing on Chromagar MSupercarba (Hylabs®) plates were isolated, identified, and subjected to modified Hodge test or CARBA-NP hydrolysis. Carbapenemase genes (blaKPC, blaVIM, blaNDM, blaIMP, blaOXA-48) were identified using Cepheid® GeneXpert Carba-R and blaIMI using homemade-PCR in the reference laboratory.

Results
Four CREs were identified from the environment: 2 CP E. cloacae blaIMI, found in both Alexander estuary and seawater of Beit-Yanai; 1 CP E. coli blaOXA-48 found in Poleg estuary, and 1 E. cloacae non-CP CRE found in Alexander estuary (Table 1, Figure 1). The 3 Enterobacter spp had similar antibiogram phenotype.

Conclusion
On two occasions CREs were easily cultivated from seawater of a popular recreational beach as well as from 2 river estuaries in Netanya. The bacterial species as well as the carbapenemase types found in the environment are quite rare compared with the clinical human epidemiology in the hospital serving the population of this district. More research is required in order to reproduce these findings, to investigate sources and persistence of rivers and coastal water pollution and to define the role “environmental” strains have in human epidemiology and disease.

Disclosures
All authors: No reported disclosures.