bluuebunny/crossref_metadata_2025_split huggingface dataset:
P-1063. SCY-247: A Second-generation IV/Oral Triterpenoid Antifungal with Extensive Tissue Distribution and Pharmacokinetics, and Low Drug-Drug Interaction Potential
Authors: Wring Steve , Borroto-Esoda Katyna , Wiederhold Nathan P , Angulo David A 
Published: January 2025

Abstract

Background
SCY-247 is an IV/oral second-generation triterpenoid anti-fungal for systemic fungal infections including multidrug resistant pathogens. Here we present translational data for nonclinical pharmacokinetics (PK) including dose-related tissue disposition in a murine C. glabrata model and correlation to reductions in fungal burden. Further, in vitro CYP450 interactions were evaluated to assess potential for clinical drug-drug interactions (DDIs).

Methods
The PK of SCY-247 was determined in rats and dogs. Plasma and tissue exposures were compared to reductions in kidney and lung fungal burden in a model of invasive C. glabrata. Neutropenic mice were infected IV with C. glabrata (∼108 yeast cells/mouse) and sacrificed on Day +7. Potential for inhibiting or inducing CYP450 isoforms was assessed in vitro using methods supportive of an FDA Investigational New Drug (IND) Application.

Results
SCY-247 has low clearance (∼10% liver blood flow) with half-life ≥15 hours following oral and IV administration to rat and dog consistent with once-daily administration in humans. Volume of distribution is ∼3 L/kg supportive of extensive tissue distribution. Exposure increased on repeat administration. Solubility of oral SCY-247 as a salt is &gt;30 mg/mL at gastric pH consistent with rapid dissolution in the stomach and rapid absorption - as demonstrated by an early Tmax (0.5-2hr) following oral administration. In a murine model of C. glabrata infection, SCY-247 demonstrated dose-related increases in exposure and corresponding reduction in fungal burden (right figure panel) with higher distribution in kidney and lung tissue compared to plasma (left figure panel). In vitro, SCY-247 did not induce human CYP450s 1A2, 2B6 or 3A4. The IC50 values for inhibition of human 2C9, 2C19 and 3A isoforms were &gt;20 μM ( &gt;10-fold higher than the anticipated clinical Cmax) supportive of low risk of DDI’s for these isoforms.

Conclusion
SCY-247 has demonstrated dose- and tissue-related exposure reductions in fungal burden, PK consistent with once daily dosing to humans and low risk for CYP450-related DDIs.

Disclosures
Steve Wring, PhD, SCYNEXIS, Inc.: Advisor/Consultant Katyna Borroto-Esoda, MS, Scynexis Inc: Advisor/Consultant Nathan P. Wiederhold, PharmD, BioMerieux: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Mycovia: Grant/Research Support|Scynexis: Grant/Research Support|Sfunga: Grant/Research Support David A. Angulo, MD, SCYNEXIS, Inc.: Board Member|SCYNEXIS, Inc.: SCYNEXIS, INC Officer and Board Member, SCYNEXIS Patents|SCYNEXIS, Inc.: Stocks/Bonds (Public Company)
P-1083. Antimicrobial Activity of Aztreonam-Avibactam and Comparator Agents against a Large Collection of Stenotrophomonas maltophilia Isolates Collected in United States Medical Centers (2019-2023)
Authors: Sader Helio S , Doyle Timothy , Winkler Marisa , Ryan Arends S J , Castanheira Mariana 
Published: January 2025

Abstract

Background
The occurrence of S. maltophilia infections has increased continuously in the last few years. We evaluated the in vitro activities of aztreonam-avibactam (ATM-AVI) and comparators against a large collection of S. maltophilia clinical isolates.
Activity of aztreonam-avibactam and comparator agents stratified by infection type.

Methods
1,400 clinical isolates were consecutively collected from 62 United States (US) medical centers. Infection sites included pneumonia (n=1,020), bacteremia (n=117), skin and skin-structure infection (SSSI; n=124), and others (n=139). Isolates were susceptibility tested by CLSI M07 broth microdilution methods. ATM-AVI was tested with AVI at fixed 4 mg/L and a pharmacodynamic/pharmacokinetic susceptible (S) breakpoint of ≤ 8 mg/L was applied for comparison.

Results
ATM-AVI inhibited 99.6% of isolates at ≤ 8 mg/L (MIC50/90, 2/4 mg/L) and demonstrated potent activity against isolates from all infection types (Table). ATM-AVI inhibited 99.7% of isolates from pneumonia and 100.0% of isolates from BSI at ≤ 8 mg/L and retained potent activity against isolates non-S to other agents commonly used to treat S. maltophilia infections. ATM-AVI was active (MIC ≤ 8 mg/L) against 100.0% of trimethoprim-sulfamethoxazole (TMP-SMX)-non-S isolates, 99.3% of isolates non-S to minocycline or levofloxacin, and 99.5% of isolates with tigecycline MIC &gt; 2 mg/L. Moreover, ATM-AVI activity remained stable during the study period; the percentages inhibited at ≤ 8 mg/L varied from 100.0% in 2019 and 2020 to 99.3% in 2023. TMP-SMX (MIC50/90, ≤ 0.12/0.5 mg/L; 96.9% S) also showed good activity against S. maltophilia. Minocycline (MIC50/90, 0.5/2 mg/L) and levofloxacin (MIC50/90, 1/8 mg/L) were active against 89.2% and 78.9% of isolates according to the 2024 CLSI breakpoint criteria.

Conclusion
ATM-AVI exhibited potent activity and broad coverage against S. maltophilia from US hospitals and its activity was not adversely affected by resistance to other agents. Our results indicated that ATM-AVI may represent a valuable option to treat S. maltophilia infections, addressing a major unmet medical need.

Disclosures
Marisa Winkler, MD, PhD, Element Iowa City (JMI Laboratories) was contracted to perform services in 2023 for &gt; 30 biotech and pharmaceutical companies: Grant/Research Support
P-1085. Characterization of Enterobacter cloacae and Citrobacter freundii Species Ccomplex Isolates with Decreased Susceptibility to Cephalosporins from United States Hospitals and Activity of Aztreonam-avibactam and Comparator Agents (2019-2023)
Authors: Sader Helio S , Doyle Timothy , Kimbrough Hank , Hubler Cory , Castanheira Mariana 
Published: January 2025

Abstract

Background
Aztreonam-avibactam (ATM-AVI) is under clinical development for treatment of Gram-negative infections, including those caused by metallo-β-lactamase (MBL) producers. We evaluated the activity of ATM-AVI and comparators against cephalosporin non-susceptible (S) E. cloacae (ECLC) and C. freundii species complex (CFC) from patients hospitalized in United States (US) medical centers.
Antimicrobial susceptibility of cephalosporin-non-susceptible E. cloacae and C. freundii species complex

Methods
A total of 43,235 Enterobacterales (1/patient) were collected via the INFORM Surveillance Program and susceptibility tested by broth microdilution in 2019-2023; among those, 5,106 (11.8%) were ECLC (n=3,732) or CFC (n=1,374). We evaluated the antimicrobial susceptibility and β-lactamase production of isolates ceftazidime-resistant (MIC ≥ 16 mg/L) or cefepime-non-S (MIC ≥ 2 mg/L). The collection includes 1,065 ECLC and 379 CFC. ATM-AVI was tested with AVI at fixed 4 mg/L and a PK/PD S breakpoint of ≤ 8 mg/L was applied for comparison. Comparator included ceftazidime-avibactam (CAZ-AVI), meropenem-vaborbactam (MEM-VAB), and cefiderocol (carbapenem-resistant [CB-R] isolates only), among others. All isolates (n=1,444) were characterized by whole genome sequencing.

Results
Isolates were mainly from urinary tract (35.5%), pneumonia (23.6%), and bloodstream infection (BSI; 16.1%). The most common ESBLs were CTX-M type (99; 49.0% of ESBL producers), SHV type (95; 47.0%), and OXA type (80; 39.6%); ≥ 2 ESBLs were identified in 67 isolates (33.1%), mainly OXA-1/30 plus a CTX-M (64 isolates; 31.7%). A carbapenemase was identified in 55 of 64 (85.9%) CB-R isolates; including KPC type (40 isolates; 62.5% of CB-R) and NDM-1 (15; 23.4% of CB-R). ATM-AVI inhibited 99.9% of isolates at ≤ 8 mg/L and showed complete activity (100.0% inhibited at ≤ 8 mg/L) against ESBL producers and CB-R isolates, including NDM producers (Table). CAZ-AVI and MEM-VAB were active against 92.1-92.6% of ESBL producers and 70.3-71.9% of CB-R isolates. Cefiderocol was active against 83.9% of CB-R isolates but only 46.7% of NDM producers.

Conclusion
ATM-AVI was highly active against cephalosporin-non-S ECLC and CFC, including MBL producers. The activities of CAZ-AVI, MEM-VAB, and cefiderocol were compromised against CB-R isolates due to the high frequency of NDM producers.

Disclosures
All Authors: No reported disclosures
P-1095. Activity of Rezafungin against Clinical Isolates of Uncommon Species of Candida spp
Authors: Winkler Marisa , Rhomberg Paul , Klauer Abigail , Castanheira Mariana 
Published: January 2025

Abstract

Background
Rezafungin (RZF) is a long-acting echinocandin recently approved by the FDA to treat invasive candidiasis (IC) and candidemia. RZF CLSI breakpoints are available for Candida albicans, C. auris (CARS), C. dubliniensis (CDUB), C. glabrata, C. krusei, C. parapsilosis (CPRP), and C. tropicalis. However, RZF susceptibility results are scarce against other Candida spp. We evaluated in vitro activity of RZF, anidulafungin (AND), caspofungin (CAS), micafungin (MCF), fluconazole (FLC), voriconazole (VRC), and amphotericin B (AMB) against less common species of Candida spp. including CARS and CDUB.

Methods
We tested 590 (1/patient) less common Candida spp. isolates from IC infections as part of the SENTRY Program (Table 1). Isolates were collected from 2020-2022 in 80 hospitals including 31 in North America, 29 in Europe, 14 in Asia-Pacific, and 6 in Latin America. Isolates were identified by MALDI-TOF MS and/or sequencing and susceptibility testing was performed using the CLSI broth microdilution method. CLSI breakpoints or epidemiologic cutoff values were applied where available.

Results
RZF displayed similar activity to other echinocandins (within ±2-fold for MIC50/90 values) against all Candida spp. tested (Table 2). The lowest RZF MIC50/90 values were noted against C. kefyr (n=51, 0.03/0.06 mg/L) and C. pelliculosa (n=10, 0.015/0.03 mg/L). Higher RZF MIC50/90 values were noted for C. guilliermondii (CGU, n=33, 1/1 mg/L) and for isolates in the CPRP complex (C. orthopsilosis (CORT) n=49, 0.5/1 mg/L, C. metapsilosis (CMET) n=25, 0.12/0.5 mg/L). The same pattern was seen with other echinocandins against these Candida spp. RZF was active against 97.7% of CDUB and 95.4% of CARS isolates applying the CLSI breakpoints. There were three CARS isolates that were resistant to RZF with MICs of 1- &gt;4 mg/L. Two of these were susceptible to CAS and one was resistant or non-wildtype to all echinocandins. For FLC 69.7% of CGU, 85.7% of CORT, 100% CMET, and only 10.8% of CARS isolates were susceptible.

Conclusion
RZF has potent in vitro activity against a large collection of less common Candida spp. as demonstrated by worldwide surveillance testing. The activity of RZF against these isolates was comparable to other echinocandins and generally better than FLC.

Disclosures
Marisa Winkler, MD, PhD, Element Iowa City (JMI Laboratories) was contracted to perform services in 2023 for &gt; 30 biotech and pharmaceutical companies: Grant/Research Support
P-1106. Sulopenem is Efficacious in a Rabbit Model of Inhalational Anthrax
Authors: Puttagunta Sailaja , Aronin Steven I , Halasohoris Stephanie , Babyak Ashley , Spencer Jade , Gray Annette , Torres Marjorie , Klimko Christopher , Cote Christopher , Hourihan Mary , Meinig James 
Published: January 2025

Abstract

Background
Sulopenem (SUL) is a penem β-lactam antibiotic in development for the treatment of resistant bacterial infections. It is available as intravenous and oral prodrug formulations, and its activity aligns with the most urgent drug-resistant antimicrobial threats defined by the CDC. SUL possesses potent activity against Enterobacterales species that encode ESBLs or AmpC-type β-lactamases that confer resistance to 3rd generation cephalosporins. SUL has also demonstrated potent in vitro activity against numerous biothreat pathogens, including Bacillus anthracis at concentrations likely to be achieved after oral dosing in humans. B. anthracis is a CDC Tier 1 Select Agent, and remains of considerable concern for biodefense. The potential for mass casualties resulting from a biothreat incident combined with the risk of antibiotic resistance necessitates development of novel medical countermeasures (MCM) for B. anthracis. Orally administered SUL was previously shown to be protective in the murine model of inhalational anthrax and provided proof-of-concept to advance the drug into the well-established rabbit model.

Methods
Female New Zealand White rabbits were challenged with a lethal dose of B. anthracis Ames spores via the inhalational route. Post-exposure prophylaxis (PEP) was initiated at 24 ±1 h postchallenge with cohorts (N=6) of animals receiving vehicle (saline, SC), ciprofloxacin (CIP) 10 mg/kg, SC or SUL 10 mg/kg, SC. This dosing regimen was informed by pharmacokinetic models to establish a human-equivalent dose. Treatment was continued BID for 14 days. Clinical progression and survival were assessed up to 30 days postchallenge.

Results
The untreated saline control group demonstrated 100% lethality with a median time to death of 48 h. Both the SUL and CIP groups demonstrated 100% survival through study termination on day 30.

Conclusion
As a MCM for inhalational anthrax, SUL would provide considerable advantages as an addition to the slate of current standards of care. Combined with positive efficacy results in two preclinical models of inhalational anthrax and advantages offered by an orally available penem antibiotic, SUL remains a promising candidate for advanced development for treating B. anthracis.

Disclosures
Sailaja Puttagunta, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company) Steven I. Aronin, MD, Iterum Therapeutics: Employee|Iterum Therapeutics: Employee|Iterum Therapeutics: Stocks/Bonds (Public Company)|Iterum Therapeutics: Stocks/Bonds (Public Company)
P-1134. Use of Respiratory Panel Polymerase Chain Reaction (RPP): Challenging Diagnostic Stewardship
Authors: Fernandez Marisol , Downey Rachel , Wesolowski Alec 
Published: January 2025

Abstract

Background
National diagnostic stewardship initiatives recommend against routine use of broad respiratory pathogen panels (RPP) for children with suspected respiratory viral illness. Use of RPP testing increased at our institution after 2020, likely related to the ongoing pandemic. Our antimicrobial stewardship team sought to meet in person with ordering services to improve diagnostic stewardship, reserving RPP for cases in which broad testing was likely to affect treatment. The aim of our study was to assess if the handshake stewardship initiative was enough to decrease the number of RPP ordered. A secondary aim was to evaluate the proportion of positive RPP tests that resulted in treatment change before and after the stewardship initiative.

Methods
This single-center, retrospective study included pediatric patients with RPP test in January to February 2023 (pre-intervention) and January to February 2024 (post-intervention). Stewardship interventions took place in June 2023. Of the ordering services included, only the emergency department (ED) and hospital service opted to meet in person. Cases were compared pre and post intervention for length of stay, race, underlying medical conditions, results of RPP, ordering service, and documented change in treatment plan based on the test results.

Results
172 and 290 RPP orders in the pre and post intervention groups were included. 101 (59%) tests were positive in the pre-intervention group compared to 136 (47%) in the post-intervention. Figure 1 shows the distribution of the ordering medical services. There was a significant decrease in RPP orders in the ED post intervention (p &lt; 0.001) (fig 1). Among patients with a positive RPP there was a treatment change in 20 (20%) pre vs 36 (26%) post-intervention (p=0.298). Figure 2 shows distribution of pathogens among positive testing. The most common viral pathogen identified in both groups was rhinovirus/enterovirus.

Conclusion
In-person handshake stewardship has the potential to guide appropriate utilization of diagnostic tests. RPP testing did not result in changes in treatment for the majority of patients regardless of handshake stewardship guidance. Future work will include developing a diagnostic algorithm to refine selection of patients to be tested.

Disclosures
All Authors: No reported disclosures
P-1143. Etiology and resistance phenotypes of blood-culture proven neonatal sepsis from two large NICUs in Mexico: a multicenter three-year retrospective analysis
Authors: Garza-Castro Abraham P , Ballesteros-Suarez Ana , Concha-Mora Lindsay A , Prieto-Baca Ericka Paulina , Tamez-Rivera Oscar 
Published: January 2025

Abstract

Background
Neonatal sepsis is a significant cause of morbidity and mortality in newborns. Etiology depends on multiple factors, particularly regional epidemiology. Current international guidelines are based on data from developed countries, which may not reflect the situation of developing regions. Microbiological surveillance in Mexican NICUs is limited, which may lead to inappropriate antimicrobial use.

Methods
This is a retrospective multicenter study conducted in two NICUs from NL, Mexico (2021-2023). Clinical and microbiological data on ≤28-day newborns with blood culture-proven neonatal sepsis were collected. Neonatal sepsis was classified as early (≤3 days) and late onset ( &gt;3 days). Descriptive statistical analyses were performed to assess microbiologic etiologies, as well as clinically-relevant resistance phenotypes (VITEK® 2).

Results
A total of 928 blood cultures from 775 patients were included. 49.0% were preterm. Mean gestational age was 35.2. Most episodes (66.9%) were classified as late-onset sepsis (Table 1). Staphylococcaceae were the most commonly identified family (48.6%). Coagulase-negative Staphylococci were the most common group (42.7%), being S. epidermidis the most common. Gram-negative bacilli were the second most common cause of neonatal sepsis (33.7 %), mostly due to K. pneumoniae (12.7%). Low prevalence of GBS was observed (3.0%). Fungal (4.1%) and enterococcal (5.2%) isolations were uncommon. The prevalence of ESBL-producing Enterobacterales were 39.4%; MRSA was 30.2% (Table 2). 4 cases (1.4%) of carbapenem-resistant Enterobacterales (CRE) and 2 cases (0.7%) of AmpC Enterobacterales were identified. Notably, 5 cases (10.4%) of vancomycin-resistant Enterococci (VRE) were identified.

Conclusion
The study reported clinical and microbiological data of blood culture-proven neonatal sepsis. In contrast with U.S. data, this study showed a lower prevalence of GBS and a significant presence of Gram-negative pathogens, alongside notable resistance profiles such as ESBL-producing Enterobacterales and VRE. Antimicrobial surveillance in developing regions is necessary in order to recognize the most common etiologies and develop treatment guidelines according to local epidemiology. VRE is a worldwide concern and should be closely monitored.

Disclosures
All Authors: No reported disclosures
P-1157. Clinical and Economic Outcome of Drugs Used in the Treatment of Pneumonia in Pediatric Population in a Tertiary Care Hospital in India-A Pharmacoeconomic Analysis
Authors: Joseph Jameskutty 
Published: January 2025

Abstract

Background
Antibiotic therapy expenses for treating pneumonia in hospitalized pediatric patients can substantially impact healthcare expenditures. We conducted a longitudinal study to investigate prescription appropriateness, predictors of treatment patterns, and key outcomes—readmission rates, length of hospital stay (LOS), and direct and indirect costs associated with diagnosing and treating community-acquired pneumonia in pediatric patients admitted to a tertiary care hospital in India.

Methods
We observed 180 children diagnosed with pneumonia and receiving antibiotic treatment upon admission to the pediatric inpatient department. We collected demographic data and prescription details, calculating direct and indirect costs. Multivariate regression analysis was employed to identify predictors of LOS and costs, while one-way ANOVA was utilized to assess cost disparities among treatment groups.

Results
Among all pneumonia admissions, mild-to-moderate cases accounted for 78.1% of cases; 66% (119 out of 180) of children had comorbid conditions alongside pneumonia. Beta-lactam antibiotics constituted the majority of prescriptions (54%), followed by aminoglycosides (20%) and macrolides (12%). Parenteral antibiotics were administered in 62.2% of cases, and switch therapy was performed in 45.5% (82) of cases. The median LOS was 3 days, with a cure rate of 95.5% (95% CI: 97-100%). Switch therapy was significantly associated with shorter LOS and substantially lower treatment costs. The average cost per pneumonia patient management was 14363 ± 782 INR ($172.26 ± 9).

Conclusion
Hospital management of pediatric pneumonia was more influenced by early discharge policies than by clinical variables.

Disclosures
All Authors: No reported disclosures
P-1173. NICU MRSA Surveillance: Implications of Retesting Versus Not Retesting MRSA-Colonized Infants
Authors: Green Julianne , Lovelace Tamika , Flynn Madelaine , Palavecino Elizabeth , Bischoff Werner 
Published: January 2025

Abstract

Background
Methicillin resistant Staphylococcus aureus (MRSA) colonization often precedes invasive infection; decolonization may prevent morbidity and mortality. MRSA surveillance protocols vary widely; at Brenner Children's Hospital (BCH), infants in the neonatal intensive care unit (NICU) undergo repeat testing after decolonization, allowing assessment of MRSA colonization/recolonization events and their relationship to invasive infection.

Methods
MRSA PCR of combined nasal/umbilical swabs from infants in the BCH NICU from 1/1/23 to 2/29/24 were performed on admission and weekly thereafter. Positive infants were decolonized with 5 days of bid intranasal mupirocin and one chlorhexidine gluconate bath (if age-eligible), then underwent repeat weekly testing along with their MRSA-negative counterparts. If/when decolonized infants subsequently tested negative by PCR, no further decolonization occurred unless/until the infant tested positive again (recolonization). Community onset (CO) colonization = a positive MRSA PCR on admission; hospital onset (HO) = at least one negative MRSA PCR prior to a positive.

Results
Of the 1061 infants admitted to the NICU, 93/1061 (9%) were MRSA PCR positive: 16/93 (17%) CO and 77/93 (83% HO), with 2.8 HO colonization events per 1,000 patient days. HO infants took an average of 5 weeks to become newly colonized; 58/77 (75%) were successfully decolonized but 36/58 (62%) of those became recolonized at least once. Long term NICU residents required multiple decolonization cycles- a maximum of 17 cycles for one infant hospitalized for 265 days. Three of four NICU MRSA bacteremia events occurred in HO infants; in each case colonization immediately preceded bacteremia.

Conclusion
Once colonized with MRSA, the majority of neonates underwent repeated decolonization/recolonization cycles. This brings into question the practice of continuous testing after initial decolonization. Events classified as recolonization may actually represent low level carriage in body sites not detected by surveillance, the inability of decolonization to fully eradicate MRSA, or detection of DNA fragments rather than viable organisms.

Disclosures
All Authors: No reported disclosures