bluuebunny/crossref_metadata_2025_split huggingface dataset:
1006. Association of Development of Pneumonia and Virulence Gene Expression in Acinetobacter baumannii Isolated from Clinical Specimens
Authors: Bae Ji Yun , Yun Ina , Jun Kang Il , Kim Chung-Jong , Lee Mi Ae , Choi Hee Jung 
Published: December 2021

Abstract

Background
Not all Acinetobacter baumannii isolated from respiratory specimens are true pathogens. Distinguishing between true pathogens and colonizers is important to initiate early treatment and to reduce the unnecessary prescription of antibiotics. To determine the microbiological factors contributing to the development of A. baumannii pneumonia, we investigated the association between the expression level of known A. baumannii virulence genes such as ompA and hisF and pneumonia.

Methods
Patients in whose respiratory specimens A. baumannii was identified between January 2018 and January 2019 in a tertiary university hospital were recruited into this study. Relevant radiologic findings and more than 5 days of susceptible antibiotic prescription started within 3 days of bacterial isolation were considered as having pneumonia. The absence of radiologic findings of pneumonia until 7 days after the isolation of A. baumannii was defined as colonization. The expression of ompA and hisF was determined with quantitative reverse-transcription polymerase chain reaction. Host factors known to be associated with pneumonia and expression levels of virulent genes were compared between the groups.

Results
Overall, 246 patients in whose respiratory specimens A. baumannii was identified were recruited into this study. Among them, 17 and 24 patients were assigned to the pneumonia and colonizer groups, respectively. In the univariable analysis, ompA, ICU stay, and mechanical ventilation were significantly associated with pneumonia (p = 0.03, &lt; 0.01, &lt; 0.01 respectively). In the multivariable analysis, mechanical ventilation was significantly associated with pneumonia (OR = 9.75, p = 0.03). ompA expression was not significantly associated with pneumonia in the multivariable analysis (OR = 1.12, p = 0.75) (Table 1). ompA and hisF were significantly associated with the 30-day in-hospital mortality (p = 0.02, &lt; 0.01).
Table 1. Univariable and multivariable analysis of factors related to pneumonia

Conclusion
The association between increased ompA expression in A. baumannii and the development of pneumonia was not statistically significant after adjusting for patient factors. However, the relatively high expression of ompA in pneumonia patients and their association with increased mortality suggests the need for larger-scale prospective studies to draw a conclusion.

Disclosures
All Authors: No reported disclosures
1009. Biofilm Formation in Acinetobacter Baumannii Clinical Isolates
Authors: Nowak Elizabeth , Bansal Ekta , Baffoe-Bonnie Anthony , Sriranganathan Nammalwar , Kerkering Thomas , Rao Jayasimha 
Published: December 2021

Abstract

Background
Multidrug resistant Acinetobacter baumannii (MDR-Ab) is a Gram-negative bacterium known for causing severe nosocomial infections, attributed in part to its formation of biofilm. Siderophore is a virulence factor known to support biofilm formation by regulating iron availability. In this study, we screened 44 isolates of MDR-Ab from our Gram-negative repository to determine the strains that phenotypically form biofilm and produce siderophore. The results were compared to Pseudomonas aeruginosa PAO1, which produces both biofilm and siderophore.

Methods
Isolates were grown overnight in minimal M9 medium supplemented with casamino acids and hydroxyquinones at 37°C. Bacterial cells were normalized (to OD 600=0.01) and a standard diluted 10-3 tube was used in the study. A 96-well plate was inoculated with 100 microliters of each isolate in quadruplicates. This process was repeated in Tygon tubes with 50 microliters of each isolate in triplicates. The plate and Tygon tubes were incubated statically for 48 hours at 30°C and then stained with crystal violet. The contents were dissolved in 33% glacial acetic acid and analyzed by spectrophotometry to measure biofilm formation. Siderophore secretion was measured in supernatants with Chrome Azurol S (CAS) reagent and production was observed on CAS agar plates.

Results
High levels of biofilm formation were observed in 8 strains of MDR-Ab in the 96-well plate (3, 4, 9, 22, 61, 1010, 1012, 1022) and 6 strains in Tygon tubes (3, 4, 16, 66, 1002, 1010) (Fig. 1). There was minimal siderophore production in MDR-Ab isolates compared to PAO1 in both the 96-well plate and Tygon tubes (Fig. 2). Only 4 strains lacked siderophore production on CAS agar and were inversely negative for the secretion in medium.
Figure 1 Biofilm formation in a 96-well plate and Tygon tubes

(A) High levels of biofilm formation were observed in MDR-Ab strain numbers 3, 4, 9, 22, 61, 1010, 1012, 1022 in the 96-well plate. (B) High levels of biofilm formation were observed in MDR-Ab strain numbers 3, 4, 16, 66, 1002, 1010 in Tygon tubes.
Figure 2 Degree of siderophore production in a 96-well plate and Tygon tubes

Siderophore production of MDR-Ab was limited compared to PAO1 after inoculation in a 96-well plate (A) and in Tygon tubes (B).

Conclusion
Many strains of MDR-Ab readily form biofilm. Overall siderophore production is lower in MDR-Ab compared to consistent production by PAO1, but this does not appear to affect MDR-Ab’s ability to form biofilm. Unlike in PAO1, biofilm formation in MDR-Ab may occur independently of siderophore production. This research serves as a basis for understanding future MDR-Ab biofilm elimination in patient catheters and indwelling devices.

Disclosures
All Authors: No reported disclosures
1012. Neutrophil Function Enhanced by Recombinant Interferon-Gamma in Newborns
Authors: Castillo-Galvan Ricardo , Soper Nicole , Bennett Monique , Thomsen Isaac 
Published: December 2021

Abstract

Background
Functional differences exist between neonatal and adult neutrophils. The incidence of infection is higher in preterm infants, and the severity of the immune impairment on the neonatal neutrophils is inversely related to gestational age. In order to recognize and combat life-threatening infections, neonates rely predominantly on the innate immune system.Neutrophils are an essential component of innate immunity, and they are the first responders against bacterial and fungal infections. Sepsis continues to be a prominent cause of neonatal mortality, especially among preterm infants. Recombinant interferon-gamma (IFNγ) effects on the immune system have included the upregulation of TLRs expression and stimulation of phagocytosis. They have been shown to reduce severe infections in children with chronic granulomatous disease.

Methods
After the protocol was IRB approved, we enrolled term infants in their first 48 hours of life (Table 1). We then obtained free flow whole-blood samples through venipuncture from the cephalic vein. Samples were incubated with and without IFNγ for 24 hours. Isolation of unperturbed neutrophils using immunomagnetics was performed for a final concentration of 1x106/mL. We then assessed the neutrophil-bacterial interaction using fluorescent GFP-Staphylococcus aureus, and quantified neutrophil killing function on a novel assay involving fibrin matrix as a more physiologic and three-dimensional (3D) environment than standard in vitro or culture-based assays. We evaluated normalized progressive ratios, 20μL/80μL, 30μL/70μL, 40μL/60μL of Neutrophil/GFP-S aureus respectively.Table 1

Results
On the 20 samples, we observed significant differences demonstrating a considerably enhanced phagocytosis on those samples with the addition of IFNγ(p&lt; 0.0001, Table 2 and Figures 1-3).

Conclusion
The phagocytic ability of neonatal neutrophils was greatly enhanced by the addition of IFNγ in term infant blood. Ongoing work will determine whether this remains true for preterm-infant neutrophils and will further delineate mechanisms of these differences. We recognized an opportunity for interferon-based immunomodulation in certain situations on this population at high risk for invasive bacterial infections.

Disclosures
Ricardo Castillo-Galvan, MD MPH, Karius Inc. (Consultant) Isaac Thomsen, MD, MSCI, Horizon Therapeutics (Consultant)
122. Impact of Infectious Diseases Consultation in Patients with Candidemia at a Large Multi-site Healthcare System Providing Telemedicine Services
Authors: Hammer Katie , Shifflet Andrew , Petteys Megan , Soman Rohit , Williamson Julie E , Medaris Leigh Ann , shahid zainab 
Published: December 2021

Abstract

Background
Candida species are the most common cause of fungemia and are associated with high mortality. Management concordant with the Infectious Diseases Society of America guidelines and infectious diseases consultation (IDC) have been shown to lower mortality in patients with candidemia. The purpose of this study was to compare in-hospital mortality at a large multi-site healthcare system, including sites providing IDC via telemedicine services, in patients with candidemia with and without IDC.

Methods
This was a retrospective, observational cohort study completed at ten sites of Legacy Atrium Health in Charlotte Metro, NC, USA; at five sites, IDC is performed via telemedicine. Adult hospitalized patients identified with candidemia were enrolled May 2018-June 2019. The primary outcome was in-hospital mortality of IDC and non-IDC patients. Secondary outcomes included obtainment of repeat blood cultures, receipt of antifungal treatment, duration of therapy, removal of central venous lines (CVC) when present, and ophthalmological examination. Fisher’s exact, Chi-Square, or two-tailed Student’s t-test were used for demographics, primary and secondary outcomes as appropriate.

Results
A total of 126 patients were enrolled: 103 (82%) in the IDC group and 23 (18%) in the non-IDC group (Table 1). Mortality was significantly lower, and rates of repeat blood culture obtainment and receipt of antifungal treatment were significantly higher in patients with IDC (Table 2). Other outcomes including duration of therapy, removal of CVC, repeat cultures within 48 hours, and ophthalmological examination were not statistically different between groups.

Conclusion
This study is the first multi-site healthcare system providing telemedicine services to evaluate the impact of IDC on candidemia mortality. Ophthalmological examination rates were low in both groups, highlighting a potential area for improvement. IDC had significantly lower mortality, higher rates of antifungal treatment, and higher rates of repeat blood culture obtainment. IDC should be strongly considered in all patients with candidemia.

Disclosures
All Authors: No reported disclosures
1061. Clinical Phage Microbiology: Evaluating Phages for Biofilm-associated Prosthetic Valve Endocarditis
Authors: Gelman Daniel , Coppenhagen-Glazer Shunit , Durst Ronen , Nir-Paz Ran , Hazan Ronen 
Published: December 2021

Abstract

Background
Prosthetic valve endocarditis (PVE) is a major treatment challenge associated with biofilm formation. It requires intensive infectious diseases consultations and prolonged therapy. Nevertheless, high mortality rates are reported even with timely diagnosis and optimal management. Bacteriophage (phage) therapy, the use of bacterial viruses as antimicrobial agents, has been suggested as a potential adjunctive treatment for PVE. This is due to the ability of lytic phages to synergize with antibiotics and to destroy biofilms. However, due to their high specificity, it is crucial to match the phages by in-vitro evaluations that simulate the clinical settings.

Methods
In this study we demonstrate this matching using an in-vitro PVE model of vancomycin-resistant Enterococcus faecalis (VRE). We have looked at the ability of the phage EFLK1, alone or in combination with antibiotics, to destroy mature biofilms from a commonly used bioprosthetic valve. In addition, we tried to predict these effects using several in-vitro phage susceptibility assays.

Results
We found that the phage EFLK1 presents a significant inhibitory effect against planktonic cultures of VRE, both alone or in combination with ampicillin or ceftriaxone. We then tested the effect of these combinations on mature biofilm grown on a standard 96-well plates. We found that the phage, or its combination with ceftriaxone, led to a two-log reduction in the bacterial viability. In contrast, the addition of ampicillin to the phage caused interference with this antibacterial effect. When tested against biofilm grown on a pericardial patch, the combination of EFLK1 and ceftriaxone was found most efficient. Finally, when tested on the whole bioprosthetic aortic valve, we found that the phage EFLK1 alone was even more efficient than its combination with ceftriaxone.
Biofilm Eradication from Bioprosthetic Aortic Valve

(A) Representation of E. faecalis biofilm formation on bioprosthetic valves. (B) Following 48-hours of growth, the valves were treated for five days by the phage EFLK1, ceftriaxone or their combination. The valves were then washed from any planktonic cells and the biofilm biomass was established by CFU enumeration.

Conclusion
This study demonstrates that a proper in-vitro matching is essential in the treatment of PVE with phages. As seen here, the phage-antibiotic combination intended for treatment should be drawn according to their efficacy on suitable models, simulating the clinical settings, with the specific pathogen, the valve material, and the used phages taken into consideration.

Disclosures
Ran Nir-Paz, MD, BiomX (Consultant)Technophage (Scientific Research Study Investigator, Advisor or Review Panel member)
1067. Identifying and Assaying New Potential Molecular Targets in Fungi Following a Novel Strategy Based on Binding Site (Dis)Similarities with Proteins of the Human Pharmacolome
Authors: Bedoya-Cardona Johann E , Rubio-Carrasquilla Marcela , Valdes-Tresanco Mario S , Ramirez-Velasquez Iliana M , Moreno Ernesto 
Published: December 2021

Abstract

Background
Invasive fungal infections account for a high burden of morbidity and mortality. This is aggravated because of the toxicity and resistance problems associated to current antifungal drugs, which in whole target only a handful of fungal molecules. In this scenario, new target identification and drug design, together with drug repurposing, represent promising strategies.

Methods
We aim to identify and test in vitro potential new therapeutic targets in fungi. Our strategy consists in identifying fungal proteins with active sites (meaning the set of residues lining the binding pocket) that are similar, but not identical!, to sites of proteins from the human pharmacolome. A high structural similarity with a human counterpart allows validation of the fungal target using cross-reactive inhibitors of the human protein. On the other hand, a few amino acid differences in the binding pocket produce local topological and chemical changes that create a "design space" for new specific inhibitors of the fungal target.

Results
Applying our own bioinformatics approach and taking advantage of the &gt;200 available crystal structures of proteins of the human pharmacolome in complex with inhibitors, we have identified ca. 30 proteins in several fungal species of the genera Histoplasma, Candida, Criptococcus, Aspergillus and Fusarium, whose binding sites share at least 70% amino acid identity with their similar binding pockets in human pharmaceutical targets. So far we have assayed in vitro, in seven different fungal species, ca. 60 known inhibitors of around twenty of the orthologous human proteins. Some of the tested inhibitors have been previously assayed in different species in drug repurposing screenings, while others, to our knowledge, have not been yet tested. Over a dozen of these compounds, targeting eight different protein targets, showed IC50 values in the micromolar order in one or across several species. In general, yeasts were more significantly affected than molds.

Conclusion
Our results point to new potential fungal targets that can be exploited for the design of new antifungal agents. Ongoing work by our group aims to identify, by virtual screening, specific inhibitors for several of these potential targets.

Disclosures
All Authors: No reported disclosures
1110. In Vivo Pharmacodynamics of Vancomycin Against Staphylococci in Young Infants
Authors: Gwee Amanda , Duffull Stephen , Zhu Derek 
Published: December 2021

Abstract

Background
Coagulase-negative staphylococci are the predominant pathogen causing late onset sepsis in young infants, however, the pharmacodynamic target for vancomycin therapy is unknown. This study aimed to determine the pharmacodynamic target of vancomycin in young infants with staphylococcal infections.

Methods
Retrospective data were collected for infants aged 0-90 days with methicillin-resistant Staphylococcus aureus (MRSA or coagulase-negative staphylococci (CoNS) bacteraemia over a 4-year period at the Royal Children’s Hospital Melbourne, Australia. Vancomycin broth microdilution minimum inhibitory concentrations (MIC) were determined. A published pharmacokinetic model was externally validated using the study dataset and a time-to-event pharmacodynamic model developed using non-linear mixed effects modelling, with the event being the first negative blood culture. Simulations were performed to determine the 24-hour trough vancomycin concentration correlating with a 90% probability target attainment (PTA) of the area under the curve in the first 24-hours (AUC0-24) exceeding the identified target.

Results
Thirty infants, 28 with CoNS and two with MRSA bacteraemia, who had 165 vancomycin concentrations determined were included. The vancomycin broth microdilution MIC was determined for 24 CoNS and one MRSA isolate, both with a median MIC of 1 mg/L (CoNS range 0.5 to 4). An AUC0-24 ≥3 00 mg/L·h was associated with a 7.8-fold increase in the chance of bacteriological cure for all staphylococci at any time point compared to an AUC0-24 &lt; 300 mg/L·h (hazard ratio 95% CI: 3.21-18.8). The 24-hour trough concentrations associated with a 90% PTA of achieving this target were &gt; 13-16 mg/L and &gt; 8-12 mg/L for 6 and 12-hourly dosing, respectively.

Conclusion
Our study found that an AUC0-24 ≥ 300 mg/L·h was associated with a 7.8-fold increase in bacteriological cure in young infants with staphylococcal bloodstream infections.

Disclosures
All Authors: No reported disclosures
1117. Tazobactam Pharmacokinetic/Pharmacodynamic Target Attainment in Healthy Volunteers and Critically-Ill Hospitalized Patients
Authors: Kalaria Shamir N , Pogue Jason M , Heil Emily , Heil Emily 
Published: December 2021

Abstract

Background
Pharmacokinetic/pharmacodynamic (PK/PD) targets and attainment are well described for beta-lactams; however, are rarely considered for beta-lactamase inhibitors. Recent evidence suggests that tazobactam (TAZ) target exposures to restore piperacillin bacteriostatic and 1 log 10 bactericidal activity against Enterobacterales are fT&gt; the piperacillin/tazobactam (TZP) MIC of 64% and 77%, respectively. The aim of this study was to evaluate TAZ probability of target attainment (PTA) of a 500 mg every 6-hour dose of tazobactam using population PK data in both healthy volunteers and hospitalized patients.

Methods
PK exposures in 1,000 patients with varying degrees of renal function were simulated using a previously described TAZ PK model developed with data from critically ill infected patients. An identical one-compartment structural model describing TAZ PK using mean population parameters observed in phase 1 PK studies was also used to simulate exposures in healthy volunteers. All simulated patients received 500 mg of TAZ as an intravenous infusion over 30 minutes or as a 3-hour extended-infusion.

Results
The table displays PTA results for patients with an estimated creatinine clearance of 60 mL/min. Based on healthy volunteer data, the highest TZP MIC where ~90% PTA was achieved for bacteriostasis was 1 mg/L and was 0.25 mg/L for bactericidal activity. These were only achieved with extended infusion administration of TAZ. In the cohort of hospitalized patients, &gt;90% PTA of TAZ exposures associated with both bacteriostasis and 1 log kill were achieved up to a MIC of 2 for intermittent infusion and up to 4 mg/L for extended infusion, due to decreased TAZ clearance in hospitalized patients. These values are significantly lower than the CLSI TZP susceptibility breakpoint of 16 mg/L, and PTA rates were lower at increased creatinine clearances.

Conclusion
fT&gt;TZP MIC target attainment is poor with maximal package insert tazobactam doses given with piperacillin, even when administered as an extended infusion. These findings have serious implications for the role of TZP in beta-lactamase producing Enterobacterales, including ESBLs, and suggest the current susceptibility breakpoints are 4-32 fold higher than those supported by PK/PD data.

Disclosures
Jason M Pogue, PharmD, BCPS, BCIDP, Merck (Consultant)QPex (Consultant)Shionogi (Consultant)Utility Therapeutics (Consultant)VenatoRX (Consultant) Emily Heil, PharmD, MS, BCIDP, Nothing to disclose
1127. Validation of an Adult and Pediatric Beta-Lactam Allergy Risk Stratification Tool
Authors: Jaffa Rupal K , Ton Minh-Thi , Forrester Jeanne , Patel Rupal , Brantley Courtney W , Campbell Jamie , Carlson Travis J , Morris Lee , Patel Niraj C , Shah Ekta , Boger Michael S , Davidson Lisa 
Published: December 2021

Abstract

Background
Penicillin allergies are commonly reported, yet more than 95% of these patients can tolerate β-lactams. A comprehensive allergy history is essential when determining which patients can safely receive a β-lactam but is rarely obtained. When available, interpretation of the history is often limited by lack of comfort in determining risk of an allergic reaction. Our antimicrobial stewardship and allergy team created a standardized allergy history questionnaire and risk stratification tool. The purpose of this study was to validate this tool by comparing risk levels assigned by various clinicians to that assigned by an allergist.

Methods
We prospectively identified 50 adult and 50 pediatric patients hospitalized between July 1, 2020 and March 31, 2021 with an allergy to penicillin, amoxicillin, ampicillin, or cephalexin. Patients with severe non-IgE mediated reactions were excluded. All patients (or caregivers) were interviewed by the same pharmacist using the allergy questionnaire. Clinicians from various subspecialties, including an adult and pediatric allergist, an adult and pediatric infectious diseases (ID) physician, an adult and pediatric hospitalist, and an adult and pediatric ID pharmacist, received anonymized completed questionnaires and the risk stratification tool, but were blinded to other clinicians’ responses. The primary endpoint was overall concordance in risk stratification between non-allergists and allergists.

Results
Overall concordance was 66% (33/50) in adult and 90% (45/50) in pediatric patients (Table 1). Concordance between individual clinicians and the allergist are shown in Figure 1. In adults, anaphylaxis, difficulty breathing, and angioedema were associated with less severe stratification by non-allergists than allergists. No clinicians stratified any pediatric patient into a lower risk category than the allergist.
Table 1. Clinician Agreement with Allergist

Figure 1. Risk Stratification Severity Compared to Allergist

Conclusion
Use of a β-lactam allergy risk stratification tool led to agreement with allergist assessment in the majority of patients. Variation in risk assignment was greater in adult patients; however, non-allergist pediatric providers assigned all patients at the same or more severe level as the allergist, indicating safety in this population.

Disclosures
All Authors: No reported disclosures