bluuebunny/crossref_metadata_2025_split huggingface dataset:
1693. Meropenem-Xeruborbactam: In Vitro Potency against Gram-Negative Bacteria in Comparison with Marketed and Investigational Beta-lactam (BL)/Beta-lactamase Inhibitor (BLI) Combinations
Authors: Lomovskaya Olga , Castanheira Mariana , Lindley Jill 
Published: December 2022

Abstract

Background
Several BLI combinations have entered into clinical testing or been approved for use but there are few comparative studies of their in vitro activity. Xeruborbactam (XER, formerly QPX7728) is a cyclic boronate BLI with potent inhibitory activity against serine and metallo-beta-lactamases (MBL). It is in clinical development in combination with meropenem (MEM). The objective of this study was to compare in vitro potency of MEM-XER to that of other investigational and approved BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant Enterobacterales (CRE) and Acinetobacter baumannii (CRAB) as well as Pseudomonas aeruginosa (PA).

Methods
The test panel of recent worldwide isolates consisted of 507 CRE including 168 MBL producers (157 NDM, 11 VIM, 1 IMP), 506 CRAB, and 506 PA that were representative of current isolates and included 65 MDR (resistant to ≥ 3 antimicrobial classes) strains. MEM-XER was tested with XER at a fixed 8 mg/L conc. and other BL/BLI combinations at their recommended BLI concentrations. MIC testing was conducted blinded to drug identity using CLSI reference methods and controlled using approved quality control bacterial strains and ranges.

Results
The MIC50 and MIC90 for MEM-XER vs CRE ranged from ≤ 0.03 mg/L to 0.06 mg/L and 0.06 mg/L to 1 mg/L, respectively. MEM-XER and cefepime-taniborbactam (FEP-TANI) were the only BL/BLIs with activity against MBL-producers; based on MIC90, MEM-XER (MIC90 of 1 mg/L) was 16-fold more potent than FEP-TANI (MIC90 of 16 mg/L). MEM-XER and sulbactam-durlobactam (SUL-DUR) were the only agents with high potency against CRAB, with MIC50/MIC90 of 0.5/4 mg/L and 1/2 mg/L. For the representative panel of PA, the potency of MEM-XER, FEP-TAN, ceftolozane-tazobactam (TOL-TAZ), imipenem-relebactam (IMP-REL), and CAZ-AVI was similar with MIC90s ranging between 2-8 mg/L; for the MDR panel, MIC90‘s were &gt; 8 mg/L for all combinations, with MER-XER, IMP-REL, TOL-TAZ, and CAZ-AVI having MIC50’s of 2-4 mg/L.

Conclusion
Compared to the marketed or investigational BL/BLIs, MEM-XERU had the broadest coverage of carbapenem-resistant gram-negative bacteria, with the most differentiating property being activity against multiple strains of MBL-producing CRE and CRAB.

Disclosures
Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support Jill Lindley, BS, AbbVie: Grant/Research Support.
1715. In Vitro Antibacterial Activity of Cefiderocol against Difficult-to-treat Resistant (DTR) Gram-negative Pathogens in United States from SENTRY Antimicrobial Surveillance Program in 2020/2021
Authors: Yamano Yoshinori , Takemura Miki , Shortridge Dee , Slover Christine M , Longshaw Christopher M , Echols Roger , Echols Roger , Echols Roger 
Published: December 2022

Abstract

Background
Difficult-to-treat resistant (DTR) isolates are defined as resistance to all first-line high-efficacy, low-toxicity antibiotics (penicillins, cephalosporins, carbapenems and quinolones), leaving physicians with limited treatment options. Cefiderocol (CFDC) is a siderophore cephalosporin with activity against a wide variety of Gram-negative bacteria, including carbapenem-resistant Enterobacterales and non-fermenters. We evaluated the in vitro activity of cefiderocol against DTR isolates collected in United States as part of SENTRY surveillance program in 2020 and 2021.
In vitro susceptibility of cefiderocol and comparator agents to DTR isolates

Methods
Susceptibility testing was performed by broth microdilution according to CLSI guidelines. All antibiotics were tested in cation-adjusted Mueller-Hinton broth (CAMHB) except for CFDC, for which iron-depleted CAMHB was used. Susceptibility rate (%) was determined according to CLSI breakpoints, and DTR pathogens were defined as being resistant to cefepime, ceftazidime ceftriaxone (only for Enterobacterales), imipenem, meropenem, ciprofloxacin and levofloxacin according to CLSI/FDA breakpoints.

Results
Among a total of 8,328 Enterobacterales, 2,241 Pseudomonas aeruginosa, and 586 Acinetobacter calcoaceticus-baumannii complex (ACB) clinical isolates from the United States, 50 Enterobacterales (0.6%), 36 P. aeruginosa (1.6%) and 114 ACB (19.5%) isolates showed a DTR phenotype, respectively. CFDC demonstrated its potent in vitro activity against these DTR isolates with MIC90 of ≤4 μg/mL with a susceptibility rate of ≥92% except for DTR ACB based on FDA breakpoint (75.4%). In contrast, MIC90s of β-lactam/β-lactamase inhibitor combination drugs showed lower activity (Table).

Conclusion
Cefiderocol demonstrated potent in vitro activity against DTR isolates of Enterobacterales, P. aeruginosa and ACB, indicating cefiderocol has high potential for treating infections caused by these difficult-to-treat strains.

Disclosures
Yoshinori Yamano, PhD, Shionogi: Employee Miki Takemura, n/a, Shionogi: Employee Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Christine M. Slover, PharmD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi: Employee Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant.
1723. MK-3866, a metallo-β-lactamase inhibitor, is not subject to efflux in Pseudomonas aeruginosa
Authors: Young Katherine , Mirza Asra , Balibar Carl , Dong Shuzhi , Bennett Frank , Jiang Jinlong , Tang Haiqun , Tudge Claire , Scott Jack , Yang Dexi , Pasternak Alexander 
Published: December 2022

Abstract

Background
Metallo-beta (β)-lactamases (MBLs) are in the class B group of β-lactamases due to zinc ions in the active site that are required for enzymatic activity. MK-3866 is a small molecule MBL inhibitor (MBLi) that restores antibacterial activity against resistant MBL-expressing gram-negative bacteria. Efflux is an important mechanism of antibiotic resistance in Pseudomonas aeruginosa (Pa). Imipenem (IMI) is not subject to efflux and neither is relebactam (REL), a β-lactamase inhibitor (BLi) of class A and C β-lactamases that is approved in combination with IMI/cilastatin. An efflux assay was devised to characterize MBLis for potentiation of IMI or cefepime (FEP) in isogenic strain pairs of efflux wild-type and multiply efflux deleted (MED) strains of Pa. Our objective was to determine if MK-3866 and related analogs are subject to efflux in Pa.

Methods
Bacterial isolates were engineered to demonstrate the ability of MBLis to be effluxed by introducing IMI metallo-β-lactamase-1 (IMP-1) (by electroporation) or Verona integron-encoded metallo-β-lactamases (VIM-1, VIM-2) (utilizing the cloning vector pFlp2) into isogenic MED and wild-type (WT) Pa isolates. Susceptibility testing was performed with IMI or FEP at a fixed concentration equal to the Pa Clinical and Laboratory Standards Institute susceptibility breakpoint for each and including a fixed 4 µg/mL of REL to inhibit class A or C enzymes, referred to as the SLICE assay. The concentration of MK-3866 and analogues required to restore susceptibility to either antibiotic in WT and MED strains was assessed.

Results
MICs to the combination of MK-3866/REL/IMI or MK-3866/REL/FEP vary by ≤4-fold between the WT and MED strain of each isogenic strain pair (Table 1). In contrast, large differential MIC values (efflux ratios) can be seen for the MK-3866 analogues A and B, with more moderate efflux ratios observed for other analogues. The exact efflux ratio depended on the MBL studied and the antibiotic partner.

Conclusion
MK-3866 showed a low potential for efflux whether IMP-1, VIM-1, or VIM-2 was expressed, in contrast to analogues of MK-3866 which exhibited differentials from nominal to extreme (≥ 128-fold) between efflux WT versus MED isolates.

Disclosures
Katherine Young, M.S., Merck & Co., Inc.: Stocks/Bonds Asra Mirza, MS, Merck & Co., Inc.: Stocks/Bonds Carl Balibar, PhD, Merck & Co., Inc.: Stocks/Bonds Shuzhi Dong, PhD, Merck & Co., Inc.: Stocks/Bonds Frank Bennett, PhD, Merck & Co., Inc.: Stocks/Bonds Jinlong Jiang, PhD, Merck & Co., Inc.: Stocks/Bonds Haiqun Tang, PhD, Merck & Co., Inc.: Stocks/Bonds Claire Tudge, PhD, Merck & Co., Inc.: Stocks/Bonds Jack Scott, PhD, Merck & Co., Inc.: Stocks/Bonds Dexi Yang, PhD, Merck & Co., Inc.: Stocks/Bonds Alexander Pasternak, PhD, Merck & Co., Inc.: Stocks/Bonds.
2298. Clinical and Demographic Characteristics of COVID-19 in Pediatric Patients in the United States
Authors: Ho Milan , Most Zachary M , Diaz Marlon , Casazza Julia A , Thakur Bhaskar , Saleh Sameh , Pickering Madison , Perl Trish M , Lehmann Christoph U , Medford Richard J , Turer Robert W 
Published: December 2022

Abstract

Background
The percentage of children infected with COVID-19 has outpaced that of adults. As children &gt;5 years are now eligible to receive vaccines, it is necessary to understand the effect of vaccination in the context of demographic characteristics, clinical factors, and variants on pediatric COVID-19 illness severity.

Methods
We conducted a descriptive study of patients ≤18 years from the Optum® COVID-19 electronic health record dataset. Patients were included if positive for COVID-19 by polymerase chain reaction or antigen testing for the first time from 3/12/2020 to 1/20/2022. We compare race and ethnicity, age, gender, US region of residence, vaccination status, body mass index (BMI), pediatric comorbidity index (PCI) (Sun, Am. J. Epidemiol. 2021), and predominant variant (by time and region) with 2-tailed t-test, multi-category chi-square test, and odds ratios (R version 4.1.2; α = 0.05). PCI is a validated comorbidity index predicting hospitalization in pediatric patients.

Results
Of all pediatric patients in our dataset, 165,468 (13.2%) tested positive for COVID-19. 3,087 (1.9%) were hospitalized, 1,417 (0.9%) were admitted to the ICU, 1545 (0.9%) received respiratory support, and 31 (0.02%) died, comparable to AAP-reported hospitalization and mortality rates in US children. Patients with severe outcomes were more likely to be younger, non-Caucasian, from the US South, unvaccinated, and have a higher PCI (Figure 1). Excluding non-severe outcomes, rates of death and ICU admission were higher in 0–4-year-olds compared to 5–11 or 12–18-year-olds (Figure 2). All patients receiving at least one dose of the vaccine survived. The odds ratio of a severe outcome is 0.11 (95% CI 0.07–0.16) in fully vaccinated patients compared to unvaccinated patients. The odds ratio of a severe outcome is 0.55 (95% CI 0.49–0.63) in partially vaccinated patients compared to unvaccinated patients.
Demographic and clinical characteristics of pediatric patients with COVID-19
Relative proportion of clinically severe outcomes within age groups, excluding non-severe outcomes

Conclusion
In this large population, incidence rate of severe outcomes from COVID-19 in pediatric patients was higher among non-Caucasian patients, living in the South, with underlying comorbid illness, and those not yet eligible for vaccination. These findings reinforce the need for a vaccine for younger patients and targeted vaccine outreach to racial and ethnic minorities and children with chronic conditions.

Disclosures
Christoph U. Lehmann, MD, Celanese: Stocks/Bonds|Markel: Stocks/Bonds|Springer: Honoraria|UTSW: Employee.
1735. The Pig Skin Commensal D. incerta Exhibits Antimicrobial Activity Against Methicillin-Resistant Staphylococcus aureus
Authors: Wei Monica , Knight Simon , Flowers Laurice , Walsh Jasmine , Grice Elizabeth A 
Published: December 2022

Abstract

Background
Methicillin-resistant Staphylococcus aureus (MRSA) infections occur commonly on skin and cause significant healthcare burden. MRSA can also stably colonize the skin and nasal passages, contributing to community spread. This colonization results in long-term interaction with the skin microbiome, which harbors a diverse community of bacteria that often use antimicrobial molecules to compete for ecologic niches. We hypothesize that the skin microbiome contains bacteria that secrete novel antimicrobial agents against MRSA.

Methods
Pigs are an established model organism for skin whose microbiome is not well explored. We mined the pig skin microbiome for bacterial species that inhibited MRSA via a modified disc diffusion assay.

Results
We find that the novel pig skin commensal D. incerta inhibits USA300 strain MRSA via a secreted antimicrobial protein that can be isolated from cell-free supernatant. Analysis of the D. incerta genome shows little homology to known antimicrobial genes clusters. The identity of the antimicrobial molecule and whether its antimicrobial activity persists in the context of MRSA skin infection remain unclear. We characterize the identity of this antimicrobial molecule via parallel genomic and biochemical approaches. Finally, we propose to test the ability of D. incerta to impede MRSA colonization and improve healing of MRSA-mediated skin infection, two clinically important skin conditions.

Conclusion
We screened the pig skin microbiome and successfully identified bacterial inhibitors of MRSA. Preliminary data suggest that the pig skin commensal D. incerta secretes a novel antimicrobial protein. Our current efforts focus on identifying this antimicrobial molecule and investigating its therapeutic potential in animal models of skin.

Disclosures
All Authors: No reported disclosures.
1736. Xeruborbactam (QPX) Potentiates the Activity of Multiple β-Lactams Against Highly Resistant Pseudomonas aeruginosa to a Greater Degree than Other β-Lactamase Inhibitors
Authors: Fleres Giuseppe , Newbrough Anthony , Hao Binghua , Chen Liang , Shields Ryan K , Clancy Cornelius J , Nguyen Minh-Hong 
Published: December 2022

Abstract

Background
Pseudomonas aeruginosa (PA) is an important pathogen notorious for antibiotic resistance. Xeruborbactam (QPX) is a potent ultra-broad-spectrum boronic acid β-lactam inhibitor (BLI) that, in combination with selected BL antibiotics, has excellent in vitro activity against carbapenem-resistant Enterobacterales (CRE), and Acinetobacter baumanii or PA producing class A/B or D carbapenemases. We evaluated QPX in combination with anti-pseudomonal BLs against clinical PA isolates from tertiary care US hospitals.

Methods
We tested PA clinical isolates resistant to ≥1 BL (imipenem (IMP), meropenem (MEM), cefepime (FEP), piperacillin-tazobactam (PIP-TAZ), aztreonam (ATM), ceftolozane-tazobactam (TOL-TZP), ceftazidime-avibactam (CZA), IMI-relebactam (IMI-REL), MEM-vaborbactam (MVB)) against QPX (in fixed concentration of 8 µg/mL) combined with anti-pseudomonal BLs. We performed whole-genome sequencing on isolates using the MiSeq platform (Illumina).

Results
Antibiograms and resistance determinants of 77 isolates tested to date are summarized in Figs 1, 2. 91% of isolates were CR; 43%, 58% and 61% were resistant to CZA, IMI-REL and MVB, respectively. No isolates produced class A/B/D carbapemases. All except 2 isolates carried PDC variants. 92% either had oprD porin single nucleotide polymorphism (SNP) or deletions. mutS mutations (present in 23% of isolates) were associated with resistance to IPM/QPX (p=.04), but not TOL-QPX or PIP-QPX. Addition of QPX significantly reduced MIC50 of IPM (32-fold), PIP (16-fold), FEP and ATM (4-fold) (all p&lt; .0001, Fig 3). Addition of QPX to MEM or TOL reduced MIC50 by 2-fold (p=.02, p&lt; .0001). QPX reduced IMP and PIP MICs more than did REL (32 vs 8-fold, p&lt; .0001) or TZP (16 vs nil, p=.0007), respectively. Addition of QPX reduced BL resistance, especially for TOL, PIP and IMP (Fig 4). We identified factors associated with BL/QPX resistance by logistic regression; for IMP/QPX: IMP resistance (p=.001), SNP in mexB (p=.01); for TOL/QPX: TOL resistance (p=.02); for PIP/QPX (SNP in mexR and mexB (p=.03).

Conclusion
QPX enhanced the activity of BLs, especially TOL and PIP, against PA with baseline resistance to BL, more so than other BLIs. TOL/QPX and PIP/QPX are less impacted by PA efflux and porin mutations than IMP/QPX.

Disclosures
Cornelius J. Clancy, MD, receives research funding paid to his institution from Astellas and Merck: Grant/Research Support|serves as an advisory Board member for Astellas, Cidara, and Scynexis, served on the advisory board for Merck, Qpex Biopharma, and Shionogi: Advisor/Consultant|Venatorx and Needham & Associates: Advisor/Consultant.
1746. Electronic medical record-embedded clinical decision support decreases inappropriate duration of antibiotics for outpatient pediatric skin and soft tissue infections
Authors: Lloyd Elizabeth C , Dillman Nicholas O , Tribble Alison C , Wu Lei , Seidl Stephannie , Burrows Heather L , Petty Lindsay A 
Published: December 2022

Abstract

Background
Most antibiotics are prescribed outside of the hospital, and up to 50% are unnecessary or inappropriate. Studies of ambulatory stewardship interventions have primarily targeted respiratory infections. We investigated the impact of an electronic medical record (EMR)-embedded clinical decision support tool on antibiotic duration for outpatient pediatric skin and soft tissue infection (SSTI).

Methods
Institutional SSTI treatment guidelines for pediatric and adult patients were developed in 7/2019, followed in 5/2020 by dedicated education for primary care pediatricians. In 12/2020, a SmartSet (EMR-embedded tool with a templated progress note and antibiotic guidance) was created for pediatrics only. In this quasi-experimental pre-post study, we included adult and pediatric patients who were prescribed antibiotics for SSTI at a primary care or surgery clinic (in person, virtual, or phone) from 7/2019 to 12/2021. Inappropriate pediatric antibiotic duration ( &gt;7 days) was compared pre- and post-intervention with interrupted time series (ITS) analysis of aggregate quarterly data. The trend in adult antibiotic duration was modeled with linear regression.

Results
We included 3,786 (948 pediatric and 2,838 adult) pre-intervention and 2,122 (469 pediatric and 1,653 adult) post-intervention visits. Pre-intervention, the percentage of inappropriate duration for pediatric patients was decreasing 1.6 percentage points per quarter (p &lt; 0.01). After SmartSet implementation, there was an immediate decrease of 10.3 percentage points (p &lt; 0.01), a relative decrease of 40% from the modeled percentage just prior to intervention (Figure 1). Inappropriate antibiotic duration for adults averaged 22.9% over the same period and did not change (p = 0.88). Figure 1Figure 1. Raw and modeled percentages of inappropriate antibiotic duration for skin and soft tissue infection before (quarters -6 to 0, encompassing Q3 2019 through Q4 2020) and after (quarters 0 to 4, encompassing Q1 2021 through Q4 2021) implementation of an EMR-embedded clinical decision support tool for pediatric patients. Time is represented in 3-month intervals, with quarter 0 being indicating the intervention at the end of December 2020.

Conclusion
Following guideline implementation and education, inappropriate antibiotic duration for ambulatory pediatric SSTI declined only modestly. An EMR-embedded clinical decision support tool was associated with an additional relative decrease of 40% in inappropriate antibiotic duration. In the same health system with comparable adult SSTI guidelines, the percentage of inappropriate antibiotic duration for adults was unchanged, suggesting timely EMR nudges can provide additional benefit over guidelines alone.

Disclosures
All Authors: No reported disclosures.
1753. Impact of a Pharmacist-Driven Home Hospital Antimicrobial Stewardship Program Pilot within a Large Community Health System
Authors: Nguyen Van , Wankum Michael , Gens Krista , Hirsch Elizabeth B 
Published: December 2022

Abstract

Background
Home Hospital (HH) is a unique and rapidly expanding care model that allows patients to receive medical therapy and monitoring through telehealth communication and nursing visits, and there are currently no published studies evaluating antimicrobial stewardship interventions in the HH setting. The goal of this study is to evaluate the impact of a pharmacist-driven antimicrobial stewardship pilot for the HH program.

Methods
This was a pre-post quasi-experimental study of adult patients enrolled in HH program between January through March in 2021 (control cohort) and in 2022 (intervention cohort), who received antibiotics (oral/intravenous) during their HH admission. Patients on long-term prophylactic antimicrobials, antifungals, external antimicrobials, or mycobacterial treatment were excluded. The antimicrobial stewardship pharmacist performed prospective audit and feedback and provided recommendations to clinicians through the electronic medical record. The primary endpoint was antibiotic use (days of therapy per 1000 patient-days). Secondary endpoints included broad-spectrum antibiotic usage; appropriateness of antibiotic indication, dosing, and duration; compliance with the institution’s outpatient antibiotic reference guide or outpatient intravenous antibiotic therapy (OPAT) monitoring; treatment failure; antibiotic-associated adverse effects; and cost of antibiotic therapy.

Results
The study included 73 and 127 patients in the control and intervention group, respectively (Figure 1). On average, the pharmacist reviewed 8 eligible patients/day. Interventions were generally well received by HH providers (Figure 2). There was no significant difference in the primary outcome. More inappropriate antibiotic indication was identified in the intervention group (46 [36%] vs. 15 [19%], p=0.01), associated with post-surgical infection prophylaxis after orthopedic procedures (Figure 3). Other secondary outcomes did not vary significantly between the groups. Figure 1:Study inclusion flowchartFigure 2:Intervention breakdownFigure 3:Infection types

Conclusion
The pilot allows for better understanding of outpatient and HH antibiotic prescribing practices to provide targeted interventions, and suggests the need for additional antimicrobial stewardship involvement to optimize antibiotic therapy in this novel care setting.

Disclosures
Elizabeth B. Hirsch, PharmD, FCCP, FIDSA, Melinta: Advisor/Consultant|MeMed: Advisor/Consultant|Merck: Advisor/Consultant|Merck: Grant/Research Support.