bluuebunny/crossref_metadata_2025_split huggingface dataset:
653. Diagnosis of Burn Sepsis Using the FcMBL ELISA: A Pilot Study in Critically Ill Burn Patients
Authors: Akers Kevin S , Schlotman Taylor , Mangum Lee C , Garcia Gerardo , Wagner Amanda , Seiler Benjamin , Cartwright Mark , Rifai Sami , Ingber Donald , Super Michael 
Published: October 2019

Abstract

Background
Infection is the leading cause of death among burn survivors, with sepsis associated with more extensive burns. Conventional diagnostic criteria are insensitive in this population. We examined a novel diagnostic ELISA based on Mannose-Binding Lectin (MBL) linked to an immunoglobulin Fc domain, which measures the concentration of Pathogen-Associated Molecular Patterns (PAMPs) across a broad range of bacterial and fungal organisms, for diagnosis and antimicrobial management of sepsis in burn patients.

Methods
We prospectively enrolled burn patients with ≥15% Total Body Surface Area (TBSA) burns into groups of noninfected, sepsis, or incipient infection, and healthy volunteers. Sepsis was defined by clinical actions responsive to sepsis. The FcMBL ELISA was performed daily using fresh whole blood. Burn subjects were sampled daily until completing antimicrobials, for 14 days if noninfected, and once for healthy controls. Differences in median PAMP concentrations between groups were assessed with the Kruskal–Wallis test, including multiple comparisons between categories.

Results
14 burn patients (3 noninfected, of whom 1 died prior to sampling, 4 Sepsis, 7 Incipient) were enrolled. The median (25–75% CI) PAMP concentration was 0.53 (0.12–1.34) ng/mL in healthy controls, 3.725 (2.53–5.94) ng/mL in noninfected, 2.22 (1.42–4.62) ng/mL in incipient, and 1.59 (0.83–2.29) ng/mL in sepsis groups. PAMP concentrations in sepsis were different (P = 0.0057) from noninfected, but incipient did not differ from noninfected (P = 0.2025). The dynamic range was lower in healthy controls (2.69 ng/mL) than incipient (4.57 ng/mL), sepsis (4.70 ng/mL), or noninfected (5.90 ng/mL). PAMP elevations correlated with clinical deterioration from infection, and were not associated with OR visits for debridement and grafting. 7 of 11 infected patients had declining PAMP levels at completion of antimicrobial therapy. 2 subjects had PAMP elevations associated with Aspergillus molds in their burn wounds.

Conclusion
The FcMBL ELISA assay may be useful for diagnosis of infection in burn patients, and may facilitate earlier discontinuation of antimicrobials. This assay may also have a novel utility for early diagnosis of Invasive Fungal Infection.

Disclosures
All authors: No reported disclosures.
656. Prioritizing Gram-Negative Bacteremia (GNB) Cases for Rapid Detection by β-Lactam Resistance (BLR) and Patient Outcomes
Authors: McCreary Erin K , Clarke Lloyd , Marini Rachel V , Nguyen Minh-Hong , Clancy Cornelius J , Shields Ryan K 
Published: October 2019

Abstract

Background
GNB is associated with significant morbidity and mortality. The availability of rapid diagnostic tests (RDTs) provides an opportunity to improve outcomes. Our goal was to review GNB and its empiric treatment at our center in order to devise rational approaches to diagnostic stewardship and use of RDTs.

Methods
All patients with GNB from 2010 to 2018 were evaluated. BLR was defined by 2019 CLSI breakpoints; phenotypes are shown in Table 1.

Results
A total of 2795 GNB cases were included (Table 2); 57% occurred within the first 24 hours of hospitalization and 29.3% in the ICU. The median length of stay (LOS) was 12 days; 17.2% of patients were re-admitted within 30 days. Fourteen- and 30-day mortality rates were 13.7% and 19.5%, respectively. Rates of death were higher (30 days; 26.3% vs. 17.1%; P < 0.001) and median LOS longer (17 vs. 11 days; P < 0.001) among patients with BLR compared with susceptible GNB. Thirty-day mortality rates were highest for CRE (30.1%) and BLR P. aeruginosa (BLR-Pa; 32.8%, Figure 1). 47.7% of BLR GNB were non-CRE/ESBL, which demonstrated higher mortality rates than CRE/ESBL (30 days; 27.6% vs. 21.2%; P = 0.048). Most common empiric regimens prescribed were piperacillin–tazobactam (TZP; 50.3%), cefepime (FEP; 24.2%), carbapenem (9.3%), or other agents (16.2%). 21.6% of GNB patients received inactive empiric treatment (IET). Empiric TZP (21.9%) was more likely to be inactive than FEP (17.5%; P = 0.05), but not a carbapenem (20.7%; P = NS). 57.6% of patients with inhibitor-resistant Enterobacteriaceae (IRE) received TZP empirically. Receipt of IET was associated with higher rates of death (30 days; 22.5% vs. 16.7, P = 0.03) and longer LOS (14 vs. 11 days; P < 0.001) than receipt of active ET. Rates of IET varied by pathogen (Figure 1).

Conclusion
IET is common against BLR GNB and associated with poor pt outcomes, highlighting the potential for RDTs and diagnostic stewardship teams (DSTs) to improve care. Genotypic RDTs detect most CRE/ESBL, but may miss nearly 50% of BLR GNB cases at our center. BLR-Pa and IRE are pathogens associated with prolonged LOS, and high rates of IET and death. These pathogens could be detected earlier by phenotypic RDTs and prioritized by DSTs to optimize early treatment regimens.

Disclosures
All authors: No reported disclosures.
658. Cost-effectiveness of Molecular Diagnostic Assays for the Therapy of Severe Sepsis and Septic Shock in the Emergency Department
Authors: Zacharioudakis Ioannis , Zervou Fainareti , Shehadeh Fadi , Mylonakis Eleftherios , Mylonakis Eleftherios 
Published: October 2019

Abstract

Background
Sepsis presents a major burden to the emergency department (ED). Because empiric inappropriate antimicrobial therapy (IAAT) is associated with increased mortality, rapid molecular assays may decrease IAAT and improve outcomes.We evaluated the cost-effectiveness of molecular testing as an adjunct to blood cultures in patients with severe sepsis or septic shock evaluated in the ED.

Methods
We developed a decision analysis model with the primary outcome the incremental cost-effectiveness ratio expressed in terms of deaths averted. Costs were dependent on the assay price and the patients’ length of stay (LOS). Three base-case scenarios regarding the difference in LOS between patients receiving appropriate (AAT) and IAAT were described.Sensitivity analyses regarding the assay cost and sensitivity, and its ability to guide changes from IAAT to AAT were performed.

Results
Under baseline assumptions, molecular testing was cost-saving when the LOS differed by 4 days between patients receiving IAAT and AAT (ICER −$7,302/death averted). Our results remained robust in sensitivity analyses for assay sensitivity ≥52%, panel efficiency ≥39%, and assay cost ≤$270. In the extreme case that the LOS of patients receiving AAT and IAAT was the same, the ICER remained ≤$20,000/death averted for every studied sensitivity (i.e., 0.5–0.95), panel efficiency ≥34%, and assay cost ≤$313. For 2 days difference in LOS, the bundle approach was dominant when the assay cost was ≤$135 and the panel efficiency was ≥77%.

Conclusion
The incorporation of molecular tests in the management of sepsis in the ED has the potential to improve outcomes and be cost-effective for a wide range of clinical scenarios.

Disclosures
Eleftherios Mylonakis, MD PhD, Sanofi-Pasteur: Grant/Research Support; T2 Biosystems: Grant/Research Support.
663. Efficacy and Safety of Lefamulin (LEF) vs. Moxifloxacin (MOX) for Legionella pneumophila (LP) in Patients with Community-Acquired Bacterial Pneumonia (CABP): Pooled Results From the Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Phase 3 Clinical Trials
Authors: Shorr Andrew F , Schranz Jennifer , Goldberg Lisa , Paukner Susanne , Das Anita F , Moran Gregory J , Sandrock Christian , File Thomas M , Alexander Elizabeth , Gelone Steven P 
Published: October 2019

Abstract

Background
LP is associated with severe CABP, rapid onset, and high morbidity/mortality. Poor outcomes in CABP have been linked to receiving inappropriate empiric therapy or delayed treatment (tx). LEF, a novel IV/oral pleuromutilin, demonstrated efficacy/safety in noninferiority studies (LEAP 1/2) vs. MOX in adults with CABP. We report efficacy/safety of LEF in patients with LP based on a pooled analyses of LEAP 1/2 data.

Methods
In LEAP 1, PORT III–V patients received LEF 150 mg IV q12h for 5–7 days or MOX 400 mg IV q24h for 7 days, with optional IV-to-oral switch (600 mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF for 5 days or oral MOX for 7 days. Both studies assessed early clinical response (ECR) at 96 ± 24 hours after first dose in the intent-to-treat (ITT; all randomized patients) population and investigator assessment of clinical response (IACR) at test-of-cure (TOC; 5–10 days after last dose) in the modified ITT (received ≥1 dose) and clinically evaluable (met predefined evaluability criteria) populations. LP was identified from baseline (BL) samples by culture, serology (IgG, Zeus L. pneumophila group 1–6 indirect fluorescent antibody assay), urine antigen testing (BinaxNOW), and real-time PCR (positive for ssrA). Efficacy analyses herein were done in the microbiological ITT (microITT, treated patients with BL CABP-causing pathogen), microITT-2 (no PCR), and microbiologically evaluable populations; safety analyses included all randomized/treated patients.

Results
Of 65 pooled microITT patients, median age was 60 y, 66% were male, 51% had a normal renal function, and 54%/25% were PORT III/IV. LP was identified in 9.3% (34/364) of LEF patients (7 [20.6%]/19 [55.9%]/8 [23.5%] PORT II/III/IV) and in 9.0% (31/345) of MOX patients (7 [22.6%]/16 [51.6%]/8 [25.8%] PORT II/III/IV), primarily by urine antigen or serology (table). Patients with LP in both tx groups achieved high and similar responses across all endpoints (Figures 1 and 2). In both tx groups, TEAE rates were low and comparable (~32%) and most were mild to moderate; 5 patients (3 LEF; 2 MOX) had treatment-emergent SAEs, all unrelated to tx. No patients died due to TEAEs; no LEF patients and 2 MOX patients discontinued tx due to TEAEs.

Conclusion
LEF appears to be as safe and effective as MOX in treating patients with LP, including when given as short-course (5 days) oral therapy.

Disclosures
All authors: No reported disclosures.
680. In vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against Pseudomonas aeruginosa from ICU and Non-ICU Wards Collected in Latin America and Globally as Part of the ATLAS Surveillance Program 2016–2017
Authors: Lob Sibylle , Kazmierczak Krystyna , Stone Gregory , Sahm Daniel F 
Published: October 2019

Abstract

Background
Ceftazidime–avibactam (CAZ-AVI) is a β-lactam/non-β-lactam β-lactamase inhibitor combination that can inhibit class A, C and some class D β-lactamases but not class B metallo-β-lactamases (MBLs). Antimicrobial resistance due to these β-lactamases and other mechanisms is increasing and is especially high in ICUs. This study evaluated the in vitro activity of CAZ-AVI and comparators against Pseudomonas aeruginosa isolates from patients in ICU and non-ICU wards.

Methods
Nonduplicate clinical isolates were collected in 2016–2017 in Asia/Pacific, Europe, Latin America, and Middle East/Africa. Susceptibility testing was performed using CLSI broth microdilution and interpreted using CLSI 2019 breakpoints. PCR and sequencing were used to determine the β-lactamase genes present in all isolates with meropenem (MEM) MIC >2 µg/mL.

Results
The activity of CAZ-AVI and comparators is shown in the table. Susceptibility rates among global P. aeruginosa were generally lower for isolates from patients in ICU than non-ICU wards, but this difference was small for CAZ-AVI (89% and 92% susceptible, respectively) and for amikacin and colistin. Among MEM-nonsusceptible (NS) isolates, CAZ-AVI was active against 72% and 70% of isolates, respectively, of which 18.4% and 18.7% were MBL-positive. CAZ AVI inhibited >83% of MEM-NS MBL-negative isolates globally. In Latin America (LA), CAZ-AVI was active against 87% of isolates from both ward types. Susceptibility rates were generally lower than the global average, especially among MEM-NS isolates and isolates from non-ICU wards. The proportion of MBL-positive isolates in the MEM-NS subset was only slightly higher in LA than globally (19.2% and 19.5% in ICU and non-ICU wards, respectively), suggesting the presence of additional resistance mechanisms. Only colistin exceeded the activity of CAZ-AVI against isolates collected globally and in LA.

Conclusion
CAZ-AVI showed potent antimicrobial activity, second only to that of colistin, against P. aeruginosa isolates from both ICU and non-ICU wards, with >88% of isolates collected globally testing as susceptible. Activity was in part compromised by MBLs, although additional resistance mechanisms may also be responsible.

Disclosures
All authors: No reported disclosures.
693. In Vitro Activity of Ceftazidime–Avibactam and Comparator Agents Against Enterobacteriaceae and Pseudomonas aeruginosa Collected From Patients with Bloodstream Infections as Part of the ATLAS Global Surveillance Program, 2014–2017
Authors: Kazmierczak Krystyna , Stone Gregory , Sahm Daniel F 
Published: October 2019

Abstract

Background
Avibactam (AVI) is a β-lactamase inhibitor with potent inhibitory activity against Class A, Class C, and some Class D serine β-lactamases. The combination of ceftazidime (CAZ) with AVI has been approved in Europe and in the United States for several indications. This study evaluated the in vitro activity of CAZ-AVI and comparators against Enterobacteriaceae (Eba) and Pseudomonas aeruginosa (Pae) isolates collected from patients with bloodstream infections as part of the ATLAS surveillance program in 2014–2017.

Methods
A total of 53416 Eba and 15050 Pae nonduplicate clinically significant isolates, including 5155 Eba and 845 Pae isolated from bloodstream infections, were collected by 167 hospital laboratories in 36 countries in Europe, Latin America, Asia/Pacific (excluding China), and the Middle East/Africa region. Susceptibility testing was performed by CLSI broth microdilution. CAZ-AVI was tested at a fixed concentration of 4 µg/mL AVI. Meropenem-nonsusceptible (MEM-NS) Eba and Pae isolates were screened for the presence of β-lactamase genes.

Results
Susceptibility data are shown in the Table. Percentages of susceptibility (% S) to the tested agents were 0.2–2.8% lower among Eba and Pae from bloodstream infections compared with isolates from combined sources in most cases. CAZ-AVI showed potent in vitro activity against all Eba bloodstream isolates and subsets of CAZ-NS and colistin-resistant (CST-R) isolates (MIC90, 0.5–2 µg/mL, 96.0–100% S). Reduced activity against MEM-NS Eba was attributable to carriage of class B metallo-β-lactamases (MBLs) because all MEM-NS MBL-negative isolates were susceptible to CAZ-AVI. CAZ-AVI also showed good in vitro activity against the majority of Pae bloodstream isolates (MIC90, 16 µg/mL, 89.5% S). Activity was reduced against CAZ-NS, MEM-NS and CST-R subsets (53.7–85.0% S), which included isolates carrying MBLs, but exceeded the activity of CAZ and MEM against these subsets by 15–65%. CST and amikacin were the only tested comparators that demonstrated comparable or greater activity against Pae bloodstream isolates.

Conclusion
CAZ-AVI provides a valuable therapeutic option for treating bloodstream infections caused by MBL-negative Eba and Pae isolates.

Disclosures
All authors: No reported disclosures.
696. Cefiderocol Susceptibility Against Molecularly Characterized Carbapenemase-Producing Gram-Negative Bacteria in North America and Europe Between 2014 and 2017: SIDERO-WT-2014 to -2016 Studies
Authors: Sato Takafumi , Tsuji Masakatsu , Kazmierczak Krystyna M , Hackel Meredith M , Echols Roger , Yamano Yoshinori , Sahm Daniel F 
Published: October 2019

Abstract

Background
Antibiotic susceptibility surveillance is the foundation for selecting treatment options as well as immediate and long-term strategies for combating antimicrobial resistance. We have conducted three surveillance studies SIDERO-WT-2014/-2015/-2016 with approximately 30,000 Gram-negative strains isolated in North America and Europe between 2014 and 2017. Here, we present the latest data of molecular analysis on acquired carbapenemase genes and antibiotic susceptibility of 3691 meropenem-nonsusceptible strains in the surveillance studies.

Methods
Meropenem-nonsusceptible strains isolated in North America (n = 1009) and Europe (n = 2,682), consisting of 1,897 Acinetobacter baumannii, 1,154 Pseudomonas aeruginosa, 447 Klebsiella pneumoniae, and 193 other Enterobacteriaceae were tested. Conventional PCR was used to detect known carbapenemases. Cefiderocol MICs were determined by broth microdilution method using iron-depleted cation-adjusted Mueller–Hinton broth.

Results
The percentages of known carbapenemases detected in 3 main pathogens are shown in the Table. In A. baumannii complex, OXA-23 was predominant followed by OXA-24 in most countries. The detection rates of VIM in P. aeruginosa were ≥40% in Greece and Russia, but none of the strains in the United States carried VIM. In K. pneumoniae, the predominant carbapenemase varied among the countries, with KPC predominating in the USA, Greece and Italy, while OXA-48-like was dominant in Russia, Spain and Turkey. Cefiderocol MIC90 were ≤4 μg/mL against these 3 pathogens in all 6 countries, except for A. baumannii strains in Russia.

Conclusion
Carbapenemase detection rates, especially in P. aeruginosa and K. pneumoniae, were quite different among the countries. Cefiderocol demonstrated potent in vitro activity against meropenem-nonsusceptible strains irrespective of the presence of specific carbapenemases.

Disclosures
All authors: No reported disclosures.
716. In vitro and In vivo Nonclinical Efficacy of AR-501 (Gallium Citrate)
Authors: Woo Jennifer , Hearne Ken , Kelson Andy , Yee Luisa , Espadas Cecilia , Truong Vu L 
Published: October 2019

Abstract

Background
Gallium nitrate citrate exhibits strong antibacterial activity and was recently shown to be safe and efficacious when intravenously administered to cystic fibrosis patients in a Phase 2 clinical study conducted by the University of Washington. We are developing an inhaled formulation of gallium citrate (AR-501), which is being tested in a Phase 1/2a clinical study. The in vitro antimicrobial activities, drug resistance profile, activities in combination with selected antibiotics, and in vivo animal efficacy if the inhaled vs. IV formulation is being presented.

Methods
MIC tests were performed on strains using the CLSI susceptibility test standards. Resistance testing exposed bacteria to 20 cycles at ranges above and below the MIC level of the drug used.SPF mice (C57BL/6J, 7–9 weeks) were inoculated intranasally with P. aeruginosa under ketamine/xylazine anesthesia. Inhalation of AR-501 used an Aeroneb Solo nebulizer. Gallium levels were determined by elemental analysis using atomic absorption spectroscopy. CFU levels were measured by enumeration of bacterial colonies following serial dilution of tissue homogenates.

Results
In vitro efficacy: MIC testing demonstrates the efficacy of AR-501 against gram (−), gram (+) and several species of mycobacteria of clinical isolates and the comparative antibacterial response with antibiotics. Resistance testing showed that AR-501 exhibited lower propensity to develop resistance than the antibiotics tested. In vivo efficacy: AR-501 Inhalation also increased the median survival time compared with IV dosing in the murine model. Bacterial clearance was increased when Tobramycin and AR-501 are co-administered. Comparative analysis of AR-501 after IH route demonstrate increased gallium levels in BAL and reduced levels in the kidney in contrast to IV route.

Conclusion
In vitro studies demonstrate the susceptibility of gram (−), gram (+) and mycobacteria pathogens and the dose range of AR-501 compared with SOC antibiotics. In vivo studies confirm the therapeutic efficacy of AR-501 in bacterial pneumonia by IH delivery and demonstrate that bacterial clearance is enhanced when SOC antibiotics are used in combination with AR-501.

Disclosures
All authors: No reported disclosures.
735. Bacteriophage Therapy Improves Survival of Galleria mellonella Larvae Injected with Vancomycin-Resistant Enterococcus faecium
Authors: El Haddad Lynn , Harb Cynthia P , Stibich Mark , Chemaly Roy F , Chemaly Roy F 
Published: October 2019

Abstract

Background
Vancomycin-resistant Enterococcus faecium (VRE) is a major multidrug-resistant organism which may cause infection or colonization in hematopoietic cell transplant (HCT) patients. The use of VRE-specific bacteriophages (phages) may potentially help eradicate VRE colonization and subsequent infections. To test the efficacy and safety of phages against VRE in vivo, a cocktail combining four phages was used in a VRE-infected larva model.

Methods
The pre-screening model Greater Wax Galleria mellonella larva was used in this study. Larvae were infected with VRE by injecting a VRE strain isolated from stools of a VRE-colonized HCT patient at a concentration of 107 colony-forming units/10 μL. A single phage (MDA1) or a phage cocktail (MDA1, MDA2, MDA3, and MDA4) were also injected at a concentration of 106 colony-forming units/10 μL. Two model groups were tested; a prevention group (PG) and a treatment group (TG). For the PG, phages were administered 1 hour before bacterial injection whereas the TG were injected with phages 1 hour post bacterial injection. Control groups included larvae injected with bacteria alone, phages alone (to measure toxicity due to phage administration), sterile media (to measure any lethal effects due to physical trauma from the injection), or without any manipulation. Every group was composed of 5 larvae. The insect’s health state was observed and scored after 8 hours of incubation at 37ºC using a published health index scoring system.

Results
Phages improved survival of VRE-infected larvae (table). Only 32% of the VRE-infected larvae survived after 8 hours of infection whereas more than 80% survived when adding phages, whether phages were administered before or after VRE infection. The phage cocktail was shown to be more effective than the single phage MDA1 in improving survival (66% vs. 82% survival). Injecting larvae with phages alone was safe as the same survival rate was observed when compared with those injected with sterile media or those without manipulation.

Conclusion
The use of larva model G. mellonella allows for rapid and efficient screening of the bacterial virulence and phage efficacy and safety. Such results highlight the feasibility and the potential impact of phage therapy on VRE colonization and infections.

Disclosures
Roy F. Chemaly, MD, MPH, FACP, FIDSA, Chimerix: Advisory Board, Research Grant; Clinigen: Advisory Board; Merck: Advisory Board, Consultant, Grant/Research Support, Research Grant, Speaker’s Bureau; Oxford immunotec: Consultant, Grant/Research Support; Shire: Research Grant, Speaker’s Bureau; Viracor: Grant/Research Support.