bluuebunny/crossref_metadata_2025_split huggingface dataset:
1031. Utility of Broad-Range Polymerase Chain Reaction Sequencing for Infectious Diseases Clinical Decision Making: A Pediatric Center Experience
Authors: Li Caitlin Naureckas , Nakamura Mari M 
Published: December 2021

Abstract

Background
Broad-range polymerase chain reaction (PCR) sequencing is a promising tool for diagnosis of infectious conditions when traditional microbiologic strategies fail to identify a pathogen. Data on the optimal clinical scenarios in which to use this tool are limited.

Methods
We assessed the rate of organism identification from broad-range PCR testing sent from our quaternary care children’s hospital between March 2017 and June 2020. We completed a retrospective chart review to evaluate patients’ baseline demographic and clinical features as well as clinical significance of results (defined as influencing antimicrobial management) by specimen type.

Results
Among 184 total samples, 111 (60%) were obtained from immunocompromised patients. The median age of patients at the time of sample collection was 11.4 years (IQR 6.5-16.0). 128/181 (71%) samples were from patients known to be on ≥ 1 antimicrobial, including prophylaxis, in the 24 hours prior to sample collection. 52/184 (28%) patients ultimately had an infectious disease diagnosed by another testing modality. The most common PCR sample types were bronchoalveolar lavage (BAL) fluid (35), lung tissue (20), and bone (14). An organism was identified from 41 (22%) samples, but positive results for only 8 samples (4%) led to a change in antimicrobial management: addition of agents in 4 cases, cessation of agents in 2, and transition from one agent to another in 2. Negative results for 3 (2%) samples led to discontinuation of antimicrobials. Organisms were identified from 11 (31%) BAL samples, of which only 2 (6%) were judged to be clinically significant. No results from lung tissue, CSF (11), skin biopsies (6), or joint fluid (4) affected antimicrobial management.

Conclusion
We found that only 6% of broad-range PCR results influenced antimicrobial management in a diverse pediatric cohort. Our findings suggest that many positive results, especially in BAL fluid, do not lead to changes in antimicrobial management. Additional work is necessary to characterize the ideal clinical scenarios in which broad-range PCR should be used as over a quarter of patients had a causative infectious disease identified by another modality.

Disclosures
All Authors: No reported disclosures
1032. Evaluation of a Multiplex Rapid Diagnostic Panel in Respiratory Specimens from Critically Ill Patients with Hospital-Acquired Pneumonia
Authors: Erich Bradley J , Kilic Abdullah , Palavecino Elizabeth , Williamson John , Johnson James , Ohl Chris , Luther Vera , Luther Vera , Beardsley James 
Published: December 2021

Abstract

Background
Rapid diagnostic tests can be a valuable aide in clinical decision-making but often cost more than traditional cultures. Prior to its implementation at our institution, we sought to evaluate the potential clinical and financial impact of using the FilmArray® Pneumonia Panel® (FP panel) in patients with hospital-acquired pneumonia (HAP).

Methods
This was a retrospective, observational, comparative study conducted at an 885-bed academic medical center. Respiratory samples obtained by bronchoalveolar lavage or tracheal aspiration from adult intensive care unit (ICU) patients with a diagnosis of HAP from Nov 2019 – Feb 2020 were tested by the FP panel in addition to routine cultures. Medical records were reviewed to determine potential changes in antimicrobial therapy if FP panel results were known by the treatment team in real time. A cost analysis was also performed incorporating the cost of the FP panel and the savings associated with the potential avoidance of antibiotics and other rapid diagnostic tests normalized per patient.

Results
56 patients met study criteria. FP panel results could have prompted a change in therapy in 36 (64.3%) patients, with a mean reduction in time to optimized therapy of approximately 51 hours. The panel identified 3 cases where the causative pathogen was not treated by empiric therapy and 34 opportunities for antibiotic de-escalation, the most common being the discontinuation of empiric vancomycin. 36 patients had been tested with a Respiratory Virus Panel, which could have been avoided if the FP panel was used. The potential therapy impact based on specific ICU and respiratory culture results is summarized in Table 1. The cost analysis calculated an additional cost of &10 per patient associated with using the FP panel.
Table 1. Potential Changes in Therapy Based on Patient Location and Culture Result

Conclusion
The FP panel could have prompted a change in therapy in about two-thirds of patients studied. Its potential benefits include quicker time to optimized therapy, reduced exposure to and cost of broad-spectrum antimicrobials, and reduced cost of other rapid diagnostic tests.

Disclosures
James Johnson, PharmD, FLGT (Shareholder) Vera Luther, MD, Nothing to disclose
1033. Skin Surface Thermal Imaging to Differentiate Cellulitis and Pseudocellulitis in the Emergency Department
Authors: Pulia Michael , Schwei Rebecca , Harwick Edward , Haleem Ambar , Hess Jamie , Glinert Robert , Keenan Thomas , McBride Joseph , Redwood Robert 
Published: December 2021

Abstract

Background
Cellulitis is misdiagnosed in up to 30% of cases, resulting in overuse of antibiotics. This represents a threat to patient safety and public health. Surface thermal imaging has been proposed as a tool to reduce errors in diagnosing cellulitis. The study objective was to compare skin surface temperature measurements between patients with cellulitis and pseudocellulitis.

Methods
We prospectively enrolled patients presenting to the emergency department (ED) with dermatologic lower extremity complaints that involved visible erythema. Using a thermal imaging camera, the maximum temperature value (Tmax) for the affected area of skin and corresponding area on an unaffected limb were captured. The Tmax gradient between the affected and unaffected limb was calculated. Gold standard diagnosis (cellulitis versus pseudocellulitis) was determined by consensus of a blinded, multidisciplinary physician review panel (two infectious disease, two dermatologists and two emergency medicine). Differences in temperature variables (Tmax and Tmax gradient) between cellulitis and pseudocellulitis were compared using t-tests.

Results
The sample included 204 participants, 59% male with an average age of 57 years. Based on expert panel consensus diagnosis, 92 (45%) of the participants had cellulitis. The cellulitis group had an average Tmax of 33.2°C and 30.2°C for affected and unaffected skin respectively, which was a significant difference of 2.9°C (CI: 2.5 to 3.6; p&lt; 0.001). The difference in the Tmax gradients between patients with cellulitis and pseudocellulitis was 2.08°C (CI: 1.46-2.70; p&lt; 0.001).

Conclusion
This represents the largest validation study of skin surface temperature differences between cellulitis and pseudocellulitis. Significant difference in temperature gradients between cases of cellulitis and pseudocellulitis suggests thermal imaging could be a useful diagnostic adjunct that can help differentiate these conditions. Such a modality could be particularly helpful in the ED setting where providers must balance diagnostic uncertainty with antimicrobial stewardship principles. Future work will identify the best performing temperature variables and determine optimal cutoff values for use in diagnostic algorithms.

Disclosures
All Authors: No reported disclosures
1039. Rapid Restoration of Bile Acid Compositions After Treatment with RBX2660 for Recurrent Clostridioides difficile Infection—Results from the PUNCH CD3 Phase 3 Trial
Authors: Papazyan Romeo , Fuchs Bryan , Blount Ken , Gonzalez Carlos , Shannon Bill 
Published: December 2021

Abstract

Background
Microbiota-based treatments are increasingly evaluated as a strategy to reduce recurrence of Clostridioides difficile infection (rCDI), and their proposed mechanisms include restoration of the microbiota and microbiota-mediated functions, including bile acid metabolism. RBX2660—a broad-consortium investigational live biotherapeutic—has been evaluated in &gt;600 participants in 6 clinical trials, with consistent reduction of rCDI recurrence. Here we report that fecal bile acid compositions were significantly restored in treatment-responsive participants in PUNCH CD3—a Phase 3 randomized, double-blinded, placebo-controlled trial of RBX2660.

Methods
PUNCH CD3 participants received a single dose of RBX2660 or placebo between 24 to 72 hours after completing rCDI antibiotic treatment. Clinical response was the absence of CDI recurrence at eight weeks after treatment. Participants voluntarily submitted stool samples prior to blinded study treatment (baseline), 1, 4 and 8 weeks, 3 and 6 months after receiving study treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 33 bile acids from all participant fecal samples received up to the 8-week time point. Mean bile acid compositions were fit to a Dirichlet multinomial distribution and compared across time points and between RBX2660- and placebo-treated participants.

Results
Clinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% versus 58.1%). RBX2660-treated clinical responders’ bile acid compositions shifted significantly from before to after treatment. Specifically, primary bile acids predominated before treatment, whereas secondary bile acids predominated after treatment (Figure 1A). These changes trended higher among RBX2660 responders compared to placebo responders. Importantly, median levels of lithocholic acid (LCA) and deoxycholic acid (DCA) showed large, significant increases after treatment (Figure 1B).

A. Bile acid compositions before (BL) and up to 8 weeks after RBX2660 treatment among treatment responders. Compositions are shown as the fraction of total bile acids classified as primary or secondary conjugated or deconjugated bile acids. B. Concentrations of lithocholic acid (LCA) and deoxycholic acid (DCA) among RBX2660 treatment responders, shown with individual samples and time point group median with interquartile ranges.

Conclusion
Among PUNCH CD3 clinical responders, RBX2660 significantly restored bile acids from less to more healthy compositions. These clinically correlated bile acid shifts are highly consistent with results from a prior trial of RBX2660.

Disclosures
Romeo Papazyan, PhD, Ferring Research Institute (Employee) Bryan Fuchs, PhD, Ferring Pharmaceuticals (Employee) Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee)
1040. Knee Explant Analysis (KnEA) Using PLG0206 in Periprosthetic Joint Infection (KnEA Study)
Authors: Huang David , Parker Dana , Pachuda Nicholas , Dobbins Despina , Steckbeck Jonathan , Urish Kenneth 
Published: December 2021

Abstract

Background
PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections (PJI). This study evaluated the rapid bactericidal activity of PLG0206 to decrease biofilm and planktonic bacteria on ex vivo infected prosthesis following removal from patients with chronic PJI.

Methods
De-identified infected prosthetics were removed from nine patients with PJI, despite chronic suppressive oral antibiotics, during a 2-stage revision procedure. Removed prosthetics were then submersed ex vivo to an expected clinical exposure of PLG0206, 1 mg/mL, for ~15 minutes. Upon completion of the 15-minute exposure, the treated explant was placed into buffer and sonicated. The sonication solution was then plated for bacterial analysis including colony forming unit (CFU) enumeration. Remaining explanted implants from the same patient served as a control and was processed similarly but without exposure to PLG0206.

Results
As shown in the Table, both Gram-positive and Gram-negative bacteria were identified from removed prosthetics during a 2-stage revision procedure of chronic PJI. Eight of ten infected prosthetics treated ex vivo to PLG0206 1 mg/mL were sterilized (No. 1-5, 8-10). Of the two infected prosthetics that were not sterilized (No. 6 and 7), one was polymicrobial (No. 6) and the other was monomicrobial (No. 7). Collectively, infected prosthetics exposed to PLG0206 demonstrated a mean 4log10 reduction (range 2 to 7).
Summary of culture and CFU log reduction among infected prosthetics exposed and not exposed to PLG0206

Table: Summary of culture and CFU log reduction among infected prosthetics exposed and not exposed to PLG0206

Conclusion
Overall, these findings support the ongoing development of PLG0206 as a local irrigation solution at 1 mg/mL concentration in the wound cavity for 15 minutes in patients undergoing treatment of a PJI occurring after total knee arthroplasty.

Disclosures
David Huang, MD, PhD, Peptilogics (Employee) Nicholas Pachuda, DPM, Peptilogics (Employee) Despina Dobbins, BS, Peptilogics (Employee) Jonathan Steckbeck, PhD, Peptilogics (Employee) Kenneth Urish, MD, PhD, Peptilogics (Grant/Research Support)
1042. Safety of Investigational Microbiota-Based Live Biotherapeutic RBX2660 in Individuals with Recurrent Clostridioides difficile Infection: Data from Five Prospective Clinical Studies
Authors: Braun Tricia , Guthmueller Beth , Harvey Adam J 
Published: December 2021

Abstract

Background
Microbiota-based treatments have shown promise to reduce recurrence, morbidity, and mortality for recurrent Clostridioides difficile infections (rCDI), but consistent and reliable safety data are needed to support regulatory approvals and broaden patient access. Here we provide cumulative safety data from 5 prospective clinical studies evaluating RBX2660—a standardized, microbiota-based investigational live biotherapeutic—for reducing rCDI.

Methods
This analysis included three Phase 2 (PUNCH CD, PUNCH CD2, PUNCH CD Open Label) and two Phase 3 trials (PUNCH CD3, PUNCH CD3-OLS ad hoc analysis). Participants were ≥18 years old with documented rCDI who completed standard-of-care oral antibiotic therapy prior to treatment with RBX2660. PUNCH CD3-OLS allowed participants with comorbidities of irritable bowel syndrome (IBS) or inflammatory bowel disease (IBD). Depending on the trial, assigned study treatment was 1 or 2 doses of RBX2660 (or placebo), administered rectally. Participants whose CDI recurred within 8 weeks were eligible for additional RBX2660 treatment. Treatment-emergent adverse events (TEAEs) were recorded for at least 6 months following last study treatment; CD2 and CD Open Label recorded TEAEs for 24 months.

Results
Among 620 participants who received at least one RBX2660 dose (assigned treatment or after recurrence), 324 (52.3%) received 1, 270 (43.5%) received 2, 14 (2.3%) received 3, and 12 (1.9%) received 4. 83 participants received blinded placebo only. A total of 1980 TEAEs were reported from 432 (69.7%) RBX2660-treated participants, compared to 174 TEAEs in 50 (60.2%) placebo-only treated participants. Most TEAEs were mild or moderate in severity, with diarrhea common in all treatment groups. No potentially life-threatening TEAEs were considered related to RBX2660. Study discontinuation due to TEAEs was minimal (&lt; 1%) with none related to RBX2660. There were no reported infections for which the causative pathogen was traced to RBX2660.

Conclusion
Across five clinical studies with consistent investigational product, RBX2660 was well-tolerated in rCDI participants. In aggregate, this data provides compelling and consistent safety data for RBX2660.

Disclosures
Tricia Braun, PharmD, Rebiotix, a Ferring Company (Employee) Beth Guthmueller, AS, Rebiotix Inc, A Ferring Company (Employee) Adam J. Harvey, PhD, Rebiotix, A Ferring Company (Employee)
1043. Activity of Mecillinam Against Enterobacterales Isolates Collected From Patients With Urinary Tract Infections (UTIs) in the USA During 2019
Authors: Hawser Stephen , Morrissey Ian , Henriksen Anne Santerre 
Published: December 2021

Abstract

Background
Mecillinam is a β-lactam antibiotic that exerts its antibacterial activity by binding to penicillin-binding protein 2. In the USA, intravenous (IV) mecillinam is in development for the treatment of complicated UTIs in the hospital setting and as step-down therapy transitioning from IV mecillinam to oral pivmecillinam so that patients can continue treatment at home. To support the clinical development of mecillinam in the USA for the treatment of both complicated and uncomplicated UTI, this observational study investigated the activity of mecillinam against Enterobacterales isolates from patients with UTI in the USA, collected during 2019.

Methods
This study evaluated the activity of mecillinam and other antimicrobial agents against 1075 selected Enterobacterales clinical isolates collected from patients with UTI in the USA during 2019. Antibiotic activity (minimum inhibitory concentration [MIC]) was determined by Clinical & Laboratory Standards Institute (CLSI) agar dilution methodology, and susceptibility was interpreted according to CLSI guidelines.

Results
Among the selected 1075 isolates, producers of extended-spectrum beta-lactamase (ESBL) represented 9.6% of Escherichia coli and 50% of Klebsiella pneumoniae. Ninety-five percent of the isolates tested were susceptible to mecillinam (Table 1). The MIC50 and MIC90 values for mecillinam were 0.25 and 2 µg/mL, respectively. Fosfomycin MIC50 and MIC90 were 1 and 32 µg/mL, respectively (97.6% of isolates were susceptible). Mecillinam showed the lowest MIC90 value of all single antibiotics tested. The highest MIC90 was 128 µg/mL for both nitrofurantoin and cefotaxime. The lowest percentage of resistance was obtained with fosfomycin (1.7%), followed by mecillinam (4%).
Table 1: Summary MIC and susceptibility data for all isolates tested (n=1075)

Conclusion
Overall, mecillinam showed excellent activity and a comparable resistance profile to fosfomycin. Resistance rates to ceftazidime, cefotaxime, ciprofloxacin and trimethoprim/sulfamethoxazole of greater than 20% are concerning due to the frequent use of these antibiotics in clinical practice to treat UTIs. Taken together, these data demonstrate that mecillinam has promising activity, with low resistance observed in Enterobacterales species causing UTIs in the USA. Clinical development of mecillinam in the USA is ongoing.

Disclosures
Stephen Hawser, PhD, Utility Therapeutics (Grant/Research Support) Ian Morrissey, Utility Therapeutics (Grant/Research Support) Anne Santerre Henriksen, MS, Advanz (Consultant)Shionogi BV (Consultant)UTILITY Therapeutics (Consultant)
1045. Safety of the Synthetic Saponin Adjuvant TQL1055: Preliminary Results from a First-in-humans Trial
Authors: Bennett Sean R , Martin Tyler 
Published: December 2021

Abstract

Background
Saponin adjuvants reliably enhance immune response to a variety of antigens, but their use is hindered by dose-limiting toxicities and supply constraints. TQL1055 is a semi-synthetic analog of the natural saponin adjuvant QS-21, rationally modified to improve tolerability and enable large-scale manufacturing. We previously showed that the combination of acellular pertussis vaccine (aP) and TQL1055 was well-tolerated and increased anti-pertussis toxin (PT) antibody responses in mice and rabbits, with a no observed adverse effect level (NOAEL) &gt; 2000 mcg/dose.

Methods
Here we report interim results from a Phase 1 first-in-humans dose-escalation study of TQL1055. Healthy adults 18 to 50 years of age were sequentially enrolled into 6 groups (n=12/group) and randomized 10:2 to receive one intramuscular dose of aP + TQL1055 or aP alone on Day 1. TQL1055 dose increased by group from 25 to 800 mcg (Figure 1). Local adverse events (AEs) (injection site pain, redness, swelling) and systemic AEs (fever, chills, headache, fatigue, myalgia, arthralgia, nausea, vomiting, diarrhea) were solicited through Day 8. Clinical laboratory panels (chemistry, hematology, coagulation) were performed on Days 1 (pre-dose), 8, and 29. Serious AEs were collected through Day 365. Antibodies to PT were assessed at all visits.
Figure 1. Study Design

Results
Blinded safety data from the first four groups (n=48) through Day 8 were analyzed, including 2 subjects/group receiving aP alone. All solicited AEs were mild or moderate (Figure 2). Local AEs, mainly injection site pain, occurred in 75% of subjects (mild 65%, moderate 10%). The incidence of total local AEs increased with TQL1055 dose, from 50% at 25 mcg to 92% at 200 mcg. The mean duration of local AEs was 1.8 days and also increased with TQL1055 dose, from 1.3 days at 25 mcg to 2.1 days at 200 mcg. Systemic AEs, mostly fatigue, headache, and nausea, occurred in 63% of subjects (mild 40%, moderate 23%), with no fevers. The mean duration of systemic AEs was 1.4 days, with no association with TQL1055 dose. No severe or serious adverse events were reported.
Figure 2. Solicited Adverse Events by Severity and TQL1055 Dose

Conclusion
In this early analysis, the safety profile of aP + TQL1055 appears similar to that of licensed aP vaccines, without severe or prolonged injection site pain. These data support further dose escalation and assessment of immunogenicity.

Disclosures
Sean R. Bennett, MD PhD, Adjuvance Technologies (Employee) Tyler Martin, MD, Adjuvance Technologies (Employee, Shareholder)
124. Establishment of a Post-Influenza Aspergillosis Model in Corticosteroid-Immunosuppressed Mice
Authors: Wurster Sebastian , García Jezreel Pantaleón , Albert Nathaniel D , Evans Scott , Kontoyiannis Dimitrios P 
Published: December 2021

Abstract

Background
Post-influenza aspergillosis (PIA) is a feared complication in patients with severe influenza, especially those receiving corticosteroids. However, validated murine models of PIA in a background of corticosteroid immunosuppression are lacking, compounding efforts to better characterize the immunopathology and treatment of this emerging entity.

Methods
8-week-old female BALB/c mice were infected with ~5% of the lethal dose of a mouse-adapted influenza A/Hong Kong/1968 (H3N2) strain (flu), delivered by aerosolization, versus control (aerosolized saline). Mice then received two intraperitoneal injections of 10 mg cortisone acetate (CA) or mock injections on days 5 and 8 after flu infection. On day 9, mice were intranasally challenged with 50,000 A. fumigatus AF-293 conidia or mock-infected with saline. Survival was monitored until day 16 and infection severity was scored using the modified murine sepsis score (MSS, 0 = healthy to 3 = moribund). Pulmonary fungal burden was determined by an 18S quantitative PCR assay on day 16 or upon death. 15-16 mice per group were assessed across 3 independent experiments.

Results
Flu infection alone caused modest early morbidity, followed by full recovery of the mice until day 16. Treatment with CA after flu infection led to 12% mortality and increased morbidity that persisted until day 16 (median MSS = 0.8). Similarly, mice infected with AF after CA treatment had 12% mortality and a median MSS of 0.7. Combination of all 3 challenges (flu, CA, and AF) led to 40% mortality and severe morbidity in surviving mice (median MSS = 2.7). Likewise, prior flu infection of CA-treated, AF-infected mice increased the pulmonary fungal burden from 27k to 80k median conidial equivalents. In contrast, mice not receiving CA treatment showed consistently low morbidity (median day-16 MSS = 0.5) and minimal fungal burden after AF challenge, regardless of prior flu infection.

Conclusion
We have established a model of PIA in CA-immunosuppressed mice that underscores the detrimental effect of corticosteroid therapy on the outcomes of PIA. In the future, we will employ this model to study the impact of various pharmacological interventions on the natural history of PIA in the background of corticosteroid immunosuppression.

Disclosures
Dimitrios P. Kontoyiannis, MD, Astellas (Consultant)Cidara Therapeutics (Advisor or Review Panel member)Gilead Sciences (Consultant, Grant/Research Support, Other Financial or Material Support, Honoraria)