bluuebunny/crossref_metadata_2025_split huggingface dataset:
1692. Ceftibuten-Xeruborbactam: In vitro Potency against Enterobacterales in Comparison with Other Oral Beta-lactams (BL) and Beta-lactamase Inhibitor (BLI) Combinations
Authors: Lomovskaya Olga , Castanheira Mariana , Lindley Jill 
Published: December 2022

Abstract

Background
The broad spectrum BLI xeruborbactam (XER, formerly, QPX7728) can be delivered IV or orally as the isobutyryloxymethyl prodrug. The prodrug form is in clinical development in combination with ceftibuten (BUT) for oral treatment of resistant gram-negative infections. The objective of this study was to compare the in vitro potency of BUT-XER to that of other investigational oral BL/BLI combinations and tebipenem (TBP) in blinded head-to-head testing against extended beta-lactamase (ESBL) producing and carbapenem-resistant Enterobacterales (CRE).

Methods
A total of 980 Enterobacterales including 515 ESBL and 460 CRE, including 195 KPC-, 97 OXA-48-like- and 168 metallo beta-lactamase (MBL) producers, were susceptibility tested by reference broth microdilution against BUT-XER (at fixed 4 mg/L) and comparator BLs or BL/BLI combinations (tested at their recommended BLI concentrations). MIC testing was conducted blinded to drug identity using CLSI reference microdilution methods and controlled using approved quality control bacterial strains and ranges.

Results
BLI inhibitor combinations and TBP had excellent potency against ESBL isolates with MIC90 in the ≤ 0.03-0.06 mg/L range for BUT-avibactam (AVI) and BUT-XER and in 0.125-0.25 mg/L range for TBP, BUT-VNTX-6236 (VNRX) and cefpodoxime (CPD)-ETX1317 (ETX) (Table). Against KPC and OXA-48-producers, BUT-XER and BUT-AVI (MIC90 0.25-0.5 mg/L) were 4-fold more potent than BUT-VNRX and CPD-ETX (MIC90 of 1-2 mg/L); TBP was not active against these strains. BUT-XER and CPD-ETX were the most potent agents against MBL-producing strains; however, anti-MBL activity of CPD-ETX was due to intrinsic antibacterial activity of ETX. TPB, BUT-AVI and BUT-VNTX did not have any relevant activity against MBL-producing strains.

Conclusion
BUT-XER had the broadest antimicrobial profile, with activity against ESBL and all carbapenemase producing isolates. Its potency against ESBL-producing isolates was comparable to the carbapenem TBP. Its in vitro potency and spectrum combined with the potential of once-daily administration based on PK studies warrants further clinical development.

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.
1703. Efficacy of Selected Metabolic Inhibitors for the Prevention and Resensitization of High-Level Daptomycin Resistance in Streptococcus mitis-oralis In Vitro and in an Ex Vivo Simulated Endocarditis Model
Authors: Kebriaei Razieh , Rybak Michael J , Lapitan Christian K , Somerville Greg A , Bayer Arnold S , Mishra Nagendra N 
Published: December 2022

Abstract

Background
Rapid development of stable, high-level daptomycin-resistance (DAP-R) is frequent among Streptococcus mitis-oralis strains during exposure to DAP in vitro and in vivo. Metabolomic analyses of in vitro-derived daptomycin-resistant (DAP-R) S. mitis-oralis strains (351D10) revealed substantial glycolytic pathway differences vs. its DAP-susceptible (DAP-S) parental strain, 351. To define translatability of such metabolic changes, we assessed combinations of DAP + strategic metabolic inhibitors likely to impact such pathways, including: oxamic acid [OXA], trimetazidine [TMZ) and 6-mercaptopurine [6-MP]. We assessed these combinations vs. our DAP-S/DAP-R isogenic strain pair both in vitro and ex vivo for: bactericidal and synergistic activities; prevention of high-level DAP-R in DAP-S cells; and/or resensitization of DAP-R cells

Methods
MICs. E test and microbroth dilution
In vitro antimicrobial combination assays. Time-kill curves (24 hr) and serial passaging in DAP (10 d).
Ex vivo IE model: SEVs (simulated endocardial vegetation’s) were quantitatively cultured at serial time-points post-exposures to DAP +/- inhibitors (0, 4, 8, 24, 32, 48 hr).

Results
In vitro , combinations of DAP + OXA or DAP + TMZ, as well as OXA or TMZ monotherapy, exerted bactericidal effect against both strains. Moreover, DAP + 6-MP yielded both a bactericidal, as well as synergistic activity against DAP-S 351 (but not against DAP-R 351 D10). None of the combinations prevented the development of DAP-R or resensitized the DAP-R strain to a DAP-S phenotype in vitro. In the ex vivo SEV model, using PK/PD simulations of humanized drug doses, DAP + OXA was the most effective regimen for both the DAP-S 351 and DAP-R 351 D10 strains; both OXA alone and DAP + OXA prevented DAP-R evolution, although not resensitizing the DAP-R strain to a DAP-S phenotype.

Conclusion
Combinations of DAP plus specific metabolic inhibitors represents a promising approach to enhance killing of S. mitis-oralis strains, as well as to potentially forestall DAP-R emergence. Also, they do provide a solid platform upon which to explore other potential metabolic modifiers for their ability to enhance the efficacy of DAP, based on definable metabolic perturbations in DAP-R S. mitis-oralis.

Disclosures
All Authors: No reported disclosures.
1707. In vitro Activities of Ceftazidime-Avibactam and Comparator Agents against Enterobacterales and Pseudomonas aeruginosa Collected &lt; 48 Hours and ≥48 Hours Post-Admission from Hospitalized Adult Patients, ATLAS Global Surveillance Program 2017-2020
Authors: Wise Mark , Stone Gregory , Sahm Daniel F 
Published: December 2022

Abstract

Background
Effective treatments for Gram-negative infections have dwindled with the emergence and dissemination of multi-drug resistant Enterobacterales (Ent) and Pseudomonas aeruginosa (Psa). Fortunately, ceftazidime-avibactam (CAZ-AVI) has activity against Ent and Psa isolates that produce Class A, C and some Class D β-lactamases. This study examined the in vitro activity of CAZ-AVI and comparators against Ent and Psa from presumed community-acquired (CA; cultured &lt; 48 h after hospital admission) and hospital-acquired (HA; cultured ≥48 h post-admission) infections collected from adult patients as part of the ATLAS surveillance program, 2017-2020.

Methods
59,904 non-duplicate Ent and 2,504 Psa isolates from adult patients (≥18 y.o.) were collected from 271 sites in 57 countries as part of ATLAS 2017-2020 (excluding North America) for which the length of hospitalization stay was specified. Antimicrobial susceptibility testing was by broth microdilution according to CLSI guidelines and analyzed using CLSI 2022 breakpoints. Ent isolates testing with meropenem MICs &gt;1 µg/mL and Escherichia coli, Klebsiella pneumoniae, K. oxytoca, K. variicola, and Proteus mirabilis testing with ceftazidime and/or aztreonam MICs &gt;1 mg/L were genetically screened for β-lactamases. For Psa, meropenem MIC &gt;2 µg/mL triggered β-lactamase screening. In 2020, approximately 25% of the meropenem non-susceptible isolates were screened.

Results
For Ent, CAZ-AVI was the most active agent examined against both the CA- and HA-infection population of isolates. The percentage of Ent isolates susceptible to CAZ-AVI was 2.6% and 5.3% higher compared to meropenem for the CA- and HA-infection sets, respectively. Considering both the CA- and HA- infection Psa isolates, CAZ-AVI was also the most active agent among comparators, showing %S rates 12.8% and 19.3% higher than meropenem, respectively.

Conclusion
Against Ent and Psa from adult patients, CAZ-AVI exhibited excellent in vitro activity regardless of whether the pathogen was isolated &lt; 48 hrs. or ≥48 hrs. post hospital admission. The slightly decreased susceptibility to CAZ-AVI for the HA Psa isolates as compared to the CA isolates, as well as the relatively low %S rates for comparators, reinforces difficult-to-treat nature of nosocomial infections.

Disclosures
All Authors: No reported disclosures.
1713. In Vitro Activities of Epetraborole, a Novel Bacterial Leucyl-tRNA Synthetase Inhibitor, Against Mycobacterium avium Complex Isolates
Authors: DeStefano Michelle S , Shoen Carolyn M , Alley M R K , Cynamon Michael H 
Published: December 2022

Abstract

Background
Epetraborole (EBO) is a boron-containing, oral inhibitor of bacterial leucyl-tRNA synthetase, an essential enzyme in protein synthesis; EBO demonstrates potent activity against nontuberculous mycobacteria. We evaluated the effects of select culture conditions on MIC determinations of EBO against isolates of M. avium complex (MAC), as well as EBO MIC90 results with Middlebrook 7H9 broth compared to those with cation-adjusted Mueller Hinton Broth (CAMHB) for 51 MAC isolates.

Methods
Six strains of MAC were used to test the in vitro activity of EBO in different conditions in a broth microdilution (BMD) assay. Activity was compared in Middlebrook 7H9 and CAMHB with 5% OADC from different manufacturers. The effects of glycerol, cations, oxyrase, varying pH levels, and increasing inoculum sizes were tested. Finally, EBO in vitro activity was tested for 51 MAC isolates in a BMD assay in both Middlebrook 7H9 and CAMHB with 5% OADC.

Results
In general, manipulation of select culture conditions caused very little variation in EBO MIC values for the 6 MAC strains except for increasing the inoculum from ∼105 to 107 CFU/mL, which caused an approximately 64x increase in the MIC. Since 1 MAC isolate out of 6 was affected by the addition of casitone, we tested 51 MAC isolates in both the minimal media Middlebrook 7H9 and the complex media CAMHB. EBO had a narrow MIC range in both broths, 0.25-8 mg/L for all isolates. The EBO modal MIC, MIC50 and MIC90 for the entire MAC panel of 51 isolates was 2 mg/L, 2 mg/L, and 8 mg/L for CAMHB and 1 mg/L, 1 mg/L, and 4 mg/L for Middlebrook 7H9, respectively (Table 1). Three clarithromycin-resistant isolates had EBO MIC values of 0.5 mg/L, 1 mg/L, and 2 mg/L suggesting that clarithromycin resistance does not affect EBO in vitro activity. In addition, amikacin resistance as determined using the Clinical Laboratory Standards Institute (CLSI) IV amikacin breakpoint (MIC ≥ 64 mg/L) had no noticeable effect on EBO MIC values. Table 1EBO In Vitro Activity Against 51 Isolates of Mycobacterium avium complex

Conclusion
The MIC distribution for the 51 MAC isolates tested was similar in both media types, indicating that CAMHB can be used to test EBO MAC susceptibilities per CLSI guidelines. Clarithromycin- and amikacin-resistant isolates demonstrated no cross-resistance with EBO.

Disclosures
Michelle S. DeStefano, n/a, AN2 Therapeutics: Grant/Research Support Carolyn M. Shoen, PhD, AN2 Therapeutics: Grant/Research Support MRK Alley, PhD, ABBOTT LABS: Stocks/Bonds|ABBVIE: Stocks/Bonds|AN2 Therapeutics: Author on epetraborole patent|AN2 Therapeutics: Salary|AN2 Therapeutics: Ownership Interest|AVANOS MED INC: Stocks/Bonds|NABRIVA THERAPEUTICS PLC: Stocks/Bonds|NOVARTIS AG: Stocks/Bonds Michael H. Cynamon, MD, AN2: Grant/Research Support|AN2: Grant/Research Support.
1724. Murine Efficacy Studies of Sulopenem Against Bacillus anthracis
Authors: Puttagunta Sailaja , Aronin Steven I , Dunne Michael , Halasohoris Stephanie A , Babyak Ashley , Hourihan Mary K , Meinig James M 
Published: December 2022

Abstract

Background
Sulopenem is a thiopenem β-lactam antibiotic being developed for the treatment of infections caused by multi-drug resistant bacteria. Sulopenem is available as intravenous and oral pro-drug formulations, and its activity aligns with the most urgent drug-resistant antimicrobial threats defined by the CDC. Sulopenem possesses potent activity against species of the Enterobacterales that encode ESBLs or AmpC-type β-lactamases that confer resistance to third generation cephalosporins. It has also demonstrated good in vitro microbiological activity against a range of bacterial pathogens including penicillin resistant S. pneumoniae, β-lactamase-producing H. influenza, and M. catarrhalis. Sulopenem is also active in vitro against a number of bio-threat pathogens at concentrations likely to be achieved after oral dosing in humans and meets criteria to be tested in the murine models of Bacillus anthracis, Yersinia pestis, Burkholderia mallei, and Burkholderia pseudomallei. The development of novel medical countermeasures (MCMs) is critical to biodefense preparedness for both military and public health.

Methods
Female BALB/c mice were challenged with B. anthracis Ames spores by whole-body aerosol, with an average challenge of 15 x LD50 and randomly divided into cohorts of 10 mice per group. At 24h post-exposure prophylaxis (PEP), which represents therapy before onset of clinical symptoms, mice were treated q8h for 14 days with vehicle (saline, IP), ciprofloxacin (30mg/kg, IP) or sulopenem etzadroxil (50, 25, or 12.5 mg/kg, PO). Mice were monitored for a total of 30 days and data analyzed to determine the effects of sulopenem etzadroxil on survival as compared to the positive treatment control, ciprofloxacin, using Log-Ranks tests for the pair wise comparisons with SAS software.

Results
Figure 1:

Conclusion
Sulopenem is active in vivo in the murine model of B. anthracis. Survival in the sulopenem treated groups was not statistically inferior to the ciprofloxacin positive control, a standard-of-care for PEP of B. anthracis. These results support further development of sulopenem for treating B. anthracis as a novel broad-spectrum and orally available MCM.

Disclosures
Sailaja Puttagunta, MD, Iterum Therapeutics: Stocks/Bonds Steven I. Aronin, MD, Iterum Therapeutics: Stocks/Bonds Michael Dunne, MD, Iterum Therapeutics: Advisor/Consultant|Iterum Therapeutics: Board Member|Iterum Therapeutics: Stocks/Bonds.
1730. Real-World Use Of Dalbavancin In A US Tertiary Referral Center
Authors: Bhugra Mudita , Chang Aaron , Polega James , Sanctis Jorgelina De , Vanderhorst Derek , Hassouna Habiba 
Published: December 2022

Abstract

Background
Dalbavancin is a lipoglycopeptide with prolonged half-life currently approved for treatment of bacterial skin and soft tissue infections. Off-label uses of dalbavancin include multiple Gram-positive infections requiring long-term antibiotics use. However, clinical data regarding Dalbavancin use in the real-world setting remains limited.

Methods
We conducted a retrospective cohort study of all adult inpatients who were administered ≥1 dose of Dalbavancin between November 2017 and March 2022.

Results
Forty-nine adults were identified. Dalbavancin was used to treat skin/soft tissue infections in 9 patients (18.8%). Off-label uses accommodated for the majority of patients, with diagnoses included: bloodstream infection (24, 50%), osteomyelitis (9,18.8%), native valve infective endocarditis (6,12.5%), native septic arthritis (6,12.5%), epidural abscess (4,8.3%), catheter-related bacteremia (3,6.3%) prosthetic joint infection (3,6.3%), and diabetic foot infection (1,2.1%). No patients with prosthetic valve infective endocarditis were identified. Staphylococcus aureus was the most common treated pathogen: MRSA (15, 35.7%), MSSA (17, 40.5%). Other pathogens included: Streptococcus (2,4.8%), Enterococcus (4,9.5%), coagulase negative Staphylococcus (5,11.9%), other gram positive (4,9.5%), none (2,4.8%). Among patients who completed therapy, overall cure, and clinical response as assessed at day 42 was achieved in 29 (96.7%) of patients,1 patient (3.3%) had relapse due to noncompliance with antimicrobial suppressive regimen. Intravenous drug use was the most common cause among patients who did not complete treatment (10, 58.8%). Adverse events included mild elevation in liver function tests, which were reversible and were not definitively related to the treatment. No rashes or infusion related reaction were reported. There were no adverse events resulting in drug discontinuation.

Conclusion
Real-world, including off-label, use of Dalbavancin appears safe and is associated with favorable treatment responses. Therefore, it should be considered as an alternative treatment approach in certain patient population including at risk population that may otherwise discharge from the hospital with no antimicrobial treatment or suboptimal oral antibiotics.

Disclosures
All Authors: No reported disclosures.
1751. Evaluation of Antimicrobial Stewardship Interventions in Primary Care Clinics
Authors: Zheng Tina , Mayer Suri , Cham Samantha , Niceforo Patrizia , Ghitan Monica 
Published: December 2022

Abstract

Background
The goal of antimicrobial stewardship is to optimize antimicrobial therapy and clinical outcomes while minimizing the unintended consequences of antimicrobial use. With the majority of antibiotics prescribed in the outpatient setting, optimizing antimicrobial prescribing across the care continuum is necessary. We aimed to evaluate the effect of antimicrobial stewardship interventions on the rate of inappropriate antibiotic prescribing in three adult primary care clinics affiliated with a tertiary care hospital.

Methods
Antibiotic prescriptions were identified by filtering common antibiotics prescribed prior to and post intervention. Prescriptions were excluded if they were prescribed pre-procedure or if the patient had a recent hospitalization within 30 days of the outpatient visit. Appropriateness of antibiotics was determined by indication, agent, dose and duration. Institutional guidelines were created for most common infections treated in the pre-intervention period. Education to outpatient providers was completed in two in-person visits.

Results
A total of 258 prescriptions were reviewed between the pre- and post-intervention periods. The majority of patients were female (73-76%) and the median age was similar between both cohorts. The most common infection treated during the pre-intervention period was urinary tract infection, whereas skin and soft tissue infection was most common in the post-intervention period. During the baseline period, the inappropriate prescribing rate was 61%. After intervention, the rate was reduced to 55%.

Conclusion
The use of outpatient antimicrobial stewardship guidelines and provider education to reinforce knowledge demonstrated reductions in inappropriate antibiotic prescribing.

Disclosures
All Authors: No reported disclosures.
1761. A Pre-Post Interventional Study on the Impact of Asynchronous Microlearning of Antimicrobial Stewardship Principles among Nursing Staff at a Large Academic Medical Center
Authors: Bobbitt Laura , Cimino Christo , Garvey Kim , Craft Leanna , Eichenseer Nicole , Nelson George E 
Published: December 2022

Abstract

Background
Nurses perform several functions that are integral for antimicrobial stewardship (AS). However, nurses are underrepresented in research and underutilized in AS interventions and implementation. Additionally, lack of education and training is consistently cited as a barrier to full nurse participation in AS activities. We used a novel approach for nursing AS education by utilizing an asynchronous mobile learning platform which delivered small amounts of information to participants daily via e-mail or text message. The objective of this study was to determine the effect of this innovated AS microlearning pedagogical approach on nursing staff knowledge, attitudes, and practices (KAP) regarding AS principles.

Methods
A course consisting of 9 case-based multiple-choice questions was developed. One question per day was delivered to participants via an institutional web-based application and followed by a brief educational explanation on associated AS principles. A KAP survey with 20 Likert scale questions on a 5-point scale was administered to participants pre-and post-intervention. Survey results were compared using a Wilcoxon signed-rank test.

Results
Of the 46 participants, most (86%) reported they administer antibiotics to &gt;50% of their patients. Of the 20 KAP questions, participant’s mean score post-intervention demonstrated statistically significant improvement for 90% (18/20) of the items. Participant’s confidence improved in key AS activities including differentiating between colonization and infection (P&lt; 0.001), identifying unnecessary urine cultures and inappropriate treatment of urinary tract infections (P&lt; 0.001), recognizing opportunities for intravenous to oral therapy conversion (P&lt; 0.001), and assessing for antibiotic-associated adverse effects (P&lt; 0.001).

Conclusion
Inclusion of nurses in AS is critical. AS nursing education through an asynchronous, brief educational format via a mobile platform resulted in statistically significant improvement in most topics covered. After course completion, participants felt more confident in their ability to participate in key AS activities. This study forms the basis for expanded AS educational efforts for all healthcare professionals.

Disclosures
All Authors: No reported disclosures.
1763. A study on the effectiveness of a pharmacist led Antifungal stewardship program, in immunocompromised patients of a tertiary care teaching hospital in South-India.
Authors: Rupali Priscilla , John Jisha Sara , Jacob Amita , Karthik Rajiv , Alexander Hanna , Selvarajan Sushil , George Biju 
Published: December 2022

Abstract

Background
Anti-fungal stewardship (AFS) is a less explored area of an anti-microbial stewardship (AMS) program as the patients prone to fungal infections are mostly immunocompromised, post-chemotherapy or post-transplant. In a Low-and- Middle income country (LMIC) like India, there is a dearth of Infectious Disease (ID) trained physicians and pharmacists. We aimed to study the effectiveness of a pharmacist led AFS program to ensure rational prescribing of antifungals via a post-prescription review and feedback method.

Methods
In this prospective interrupted time series analysis from June 2021 to November 2021, AFS was done on adult in-patients in the department of Hematology in a tertiary care teaching hospital in South India. The study had a pre-intervention phase and intervention phase of 3 months each. In the pre-intervention phase, patients on anti-fungal therapy &gt; 48 hours were identified and base line data were collected and no recommendations were given. In the intervention phase, in those on antifungals &gt;48 hours, appropriate recommendations were made with regard to modification and discontinuation of the anti-fungals based on patients’ clinical condition under the supervision of an ID physician. Acceptance and impact of the intervention were monitored and recorded.
METHOD OF THE STUDY
The study was a prospective study with 2 phases : pre-intervention and intervention. In the intervention phase, the appropriateness of the Anti-fungal therapy was analyzed and recommendations were given.

Results
A total of 193 patients were analyzed over 6 months, of which 107 patients with a mean age of 42.1 ± 14.2 belonged to the pre-intervention phase and 86 patients aged 40.2 ±12.6 years were in the intervention phase. There was no statistically significant difference in the in-hospital mortality [26.16% vs 23. 25% (p = 0.64)] between the two groups. In the intervention phase, 15 (17.44%) prescriptions were found to be inappropriate. Among these 66% of the recommendations were accepted by the treating physician. The days of therapy per 100 patient days were calculated for each individual anti-fungal drug and there was a significant reduction in consumption of Anidulafungin [29.648 Vs 14.28 (p &lt; 0.0007)], Amphotericin B [42.05 Vs 22.18 (p&lt; 0.0001)] and Voriconazole [56.41 Vs 35.77 (p&lt; 0.00001)] in the intervention phase.

Outcome measurements

Conclusion
A pharmacist led AFS program resulted in statistically significant reduction in the consumption of antifungals, without a significant difference in the in-hospital mortality.

Disclosures
Priscilla Rupali, MD, DTM&H, PFIZER: Grant/Research Support|PFIZER: Grant/Research Support.