bluuebunny/crossref_metadata_2025_split huggingface dataset:
374. Early Discontinuation of Empiric Antibiotics for Febrile Neutropenia in Pediatric Allogeneic Haploidentical Hematopoietic Cell Transplant Recipients
Authors: Castejon Ramirez Sandra , Ferrolino Jose Amadeo A , Allison Kim J , Merritt Pamela , Peterson Megan , Cole Amanda , Davis Amber , Gowen Ashleigh , Tang Li , Luo Guangjin , Dallas Ronald H , Wattier Rachel L , Hijano Diego R , Maron Gabriela 
Published: January 2025

Abstract

Background
Febrile neutropenia (FN) occurs in 80-90% of haploidentical hematopoietic cell transplants (haplo-HCT), but most patients do not have documented infections. Empiric antibiotics are frequently continued until neutrophil recovery, even when there is no evidence of infection. Shorter antibiotic courses to decrease antibiotic exposure have been studied in adult HCT recipients and have demonstrated safety compared to conventional management. In 2017 we implemented a strategy to discontinue antibiotics at ≤ 72 h in stable haplo-HCT patients with FN and no evidence of infection. In this study, we evaluate the implementation and outcomes of this practice.Figure 1.A. Mean antibiotic-free days across the study period. B. Individual antibiotic-free days in EAD and LAD

Methods
This single-center retrospective cohort included patients &lt; 24 years old who underwent haplo-HCT from 2010 to 2022 with ≥ 1 episode of FN and no documented infection. They were classified by time period as follows: late antibiotic discontinuation (LAD) vs. early antibiotic discontinuation &lt; 72 h (EAD). The primary outcome was antibiotic-free days. The secondary outcomes were subsequent breakthrough bloodstream infection (BSI), intensive care unit (ICU) admission, septic shock, mortality, and practice fidelity (adherence) and sustainability.Figure 2.Fidelity to implemented practice across time

Results
We included 230 patients (117 in LAD, 113 in EAD). No differences in age, sex, or race were observed. A higher proportion of patients received myeloablative conditioning regimens in LAD (p &lt; 0.01, Table 1). There were more antibiotic-free days after EAD implementation (Figure 1), but no differences in the incidence of breakthrough bloodstream infections (EAD: 6.1%, LAD: 5.1%, p= 0.81) or other adverse clinical outcomes. There was no infection-related mortality in either group (Table 1). The fidelity (adherence) to recommended practice of discontinuing antibiotics ≤72 hours was 61.6%, with increase over time (Figure 2).

Conclusion
Implementation of EAD strategy for FN in haplo-HCT patients led to an increase in antibiotic-free days during the first 30 days post-HCT. Adverse clinical outcomes were infrequent in both groups and did not significantly increase after EAD. Prospective multicenter studies are required to evaluate the safety of EAD strategies.

Disclosures
Diego R. Hijano, MD, MSc, FDA: Grant/Research Support|Merck: Grant/Research Support|National Institute of Health: Grant/Research Support Gabriela Maron, MD, MS, Astellas Inc: Grant/Research Support|NIH: Grant/Research Support|SymBio Pharma: Advisor/Consultant|SymBio Pharma: Grant/Research Support
P-997. Congenital Cytomegalovirus and Hearing Loss and Response to Treatment with Valganciclovir
Authors: Mark Salzman B , Lin Lisa C 
Published: January 2025

Abstract

Background
Congenital cytomegalovirus (CMV) occurs in about 1 in 200 babies and is the leading non-genetic cause of sensorineural hearing loss (SNHL) in children in the United States. Approximately 50% of children with SNHL secondary to CMV have progression of their hearing loss. Data on the effectiveness of valganciclovir in the treatment of infants with congenital CMV with isolated hearing loss at birth is limited.

Methods
All newborns who did not pass their newborn hearing screening at birth between 2019-2023 were included and tested for CMV by a nucleic acid test from saliva and if positive confirmed from urine. All infants with CMV detected in urine had a Brainstem Auditory Evoked Response (BAER) test by 2-3 weeks of life and if hearing loss was confirmed, offered treatment with valganciclovir for 6 months. Infants who only had CMV detected in the saliva were not included.

Results
204,680 newborns received hearing screens between 2019-2023. 7147 (3.5%) did not pass their hearing screening. 509 (7.1%) had hearing loss confirmed on BAER testing. 46 of the 7147 infants who did not pass their initial hearing screen had CMV detected in saliva and 17 of those had CMV detected in urine. 5 patients never received a urine test and were lost to follow-up. Among 17 cases with confirmed congenital CMV, 9 had confirmed hearing loss, 7 had normal hearing, and one lost to follow-up. 12 of the 17 cases were treated with valganciclovir, 8 with confirmed hearing loss, 3 with normal hearing, and one unknown. Among the 8 treated with hearing loss, 3 had progression of hearing loss, one improved, one was unchanged, and 3 lost to follow-up. Among the 7 with congenital CMV and normal hearing at birth, 3 were treated with valganciclovir and 2 remain with normal hearing with one to be determined. Among the 4 not treated, 3 remain with normal hearing and one was lost to follow-up.
Among the 6638 with normal hearing on follow-up, 7-13 had congenital CMV (1 in 511-948). Among the 509 with confirmed hearing loss, there were 9 (1.8%) who had congenital CMV.

Conclusion
Congenital CMV was found in only 1.8% of newborns with hearing loss and about 0.15% of newborns without hearing loss. Treatment with valganciclovir did not appear to be beneficial in preventing the progression of hearing loss in some newborns but the numbers were too small to reach a conclusion.

Disclosures
All Authors: No reported disclosures
P-999. Novel diagnostic tools to enhance early detection of congenital Chagas disease
Authors: Nolan Melissa , Lic Stanley Rodriguez , Katie Lynn M , Meyer Madeleine M , Lee Chris , Campbell Berry 
Published: January 2025

Abstract

Background
Chagas disease (CD), Trypanosoma cruzi infection, is a neglected vector-borne disease endemic in Latin America for which &lt; 1% of cases have been treated. WHO estimates that ∼9,000 infected neonatal cases occur annually via vertical transmission—US CDC estimates up to ∼300 incident neonatal cases annually. Maternal and neonatal misdiagnosis are principally attributed to the paucity of accurate diagnostic tools for this complex chronic parasitic infection, with current guidelines requiring confirmation testing at &gt;9 months of age—a significant barrier for vulnerable populations already experiencing healthcare access limitations.

Methods
A maternal-infant CD program was established in Sonsonate, El Salvador through a collaboration between flagship universities and the Ministry of Health. Employing machine learning methods, we developed a histology-based parasite image recognition application to aid in triaging of at-risk cases. Second, we developed an innovative diagnostic workflow integrating Bayesian statistics and novel digital PCR methods to validate a new diagnostic tool for enhanced disease detection among mothers-infants.

Results
Since March 2022, a 6% seropositivity was noted among parturition women. Maternal CD status was significantly associated with pregnancy complications and neonatal complications (Apgar &lt; 9 at 1 min and at 5 mins, NICU admission, et al). A customized convolutional neural network design employed on bifurcated Giemsa-stained blood smears revealed &gt;90% parasite detection accuracy. Lastly, McNemar’s statistic found significantly increased diagnostic capacity between our novel dPCR approach vs conventional qPCR. Specifically, dPCR was 2.74 times more likely to detect parasitic DNA in maternal blood than qPCR; 9.5 times more likely in placental tissue; 4.5 times more likely in cord tissue.

Conclusion
Congenital transmission is a growing international clinical concern. Our preliminary results provide compelling evidence for both the need of novel diagnostics and support for incorporation of study-developed cutting-edge diagnostics to aid in timely clinical management of congenital CD.

Disclosures
All Authors: No reported disclosures
P-1045. Decreasing Frequency of Invasive Aspergillus due to Aspergillus terreus Coinciding with the Introduction of Anti-Mold Azole Prophylaxis: A 30 Year Study of Invasive Aspergillosis at a Tertiary Cancer Center
Authors: Dagher Hiba , Hachem Ray Y , Haddad Andrea , Jiang Ying , Kontoyiannis Dimitrios P , Shrestha Jishna , Sherchan Robin , Lamie Peter , Makhoul Jennifer , Chaftari Patrick , Chaftari Anne-Marie , Raad Issam I 
Published: January 2025

Abstract

Background
Invasive aspergillosis (IA) is a significant cause of morbidity and mortality in patients with haematological malignancy (HM) patients and hematopoietic stem cell transplant (HSCT) recipients. A. terreus is well known to be more resistant to amphotericin B regimens and is associated with worse outcomes as compared to non-terreus Aspergillus species. After the first introduction of effective anti-mold azole in May 24,2002, there has been limited data showing the change in in etiology of culture documented IA. We retrospectively reviewed all HM and HSCT patients with a positive culture of Aspergillosis who were treated for either definite or probable IA over the past three decades (1993-2023).

Methods
We compared baseline characteristics, antifungal prophylaxis and treatment between patients infected with A. terreus and those infected with non-terreus Aspergillus between July 1993 and July 2023 with a follow up period of 12 weeks. We examined the rate of A. terreus across the 3 decades 1993 – 2003, 2004 – 2013, and 2014-2023.

Results
A total of 699 patients with culture -documented IA were analyzed, 537 with A. non-terreus species and 162 with A. terreus. Type of underlying malignancy (HM and HSCT), neutropenia as well as GVHD were similar in both groups. Anti-mold prophylaxis was similar in both groups. After the introduction of anti-mold azoles, the rate of A. terreus decreased significantly from 35.9 % between 1993-2003 to 11.2% between 2004-2013 (p&lt; 0.0001) and from 35.9% between 1993-2003 to 16.7% between 2014-2023 (p&lt; 0.0001). ICU stay and mechanical ventilation were more common among patients with A. terreus (p=0.002). All-cause mortality at 6 weeks and at 12 weeks was significantly higher in patients with A. terreus (p&lt; 0.01). Similarly, IA-associated 6 weeks mortality was significantly higher among patients with A. terreus (43 % vs 29%, p&lt; 0.01).

Conclusion
The rate of IA due to A. terreus decreased significantly with the introduction of anti-mold azoles. However, IA caused by A. terreus continues to have poor prognosis in HM patients.

Disclosures
Dimitrios P. Kontoyiannis, MD, AbbVie: Advisor/Consultant|Astellas Pharma: Advisor/Consultant|Astellas Pharma: Grant/Research Support|Astellas Pharma: Honoraria|Cidara Therapeutics: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Knight: Advisor/Consultant|Merck: Advisor/Consultant|Scynexis: Advisor/Consultant
P-1050. A Decade of Pneumocystis jirovecii Pneumonia: a Single-Center Retrospective Analysis in Both HIV and Non-HIV Populations
Authors: Oliveira Susana Ramos , Bacelar Clara , Azeredo Constança , Gonçalves Maria João , Duarte Frederico , Pena Eduarda , de Abreu Ricardo Correia , Jordão Sofia 
Published: January 2025

Abstract

Background
Pneumocystis jirovecii pneumonia (PJP) is a life-threatening opportunistic disease, commonly occurring in individuals with human immunodeficiency virus (HIV) or immunodepression. This study analyzes PJP cases in our local setting, detailing the epidemiological and clinical characteristics, as well as prognosis, and underlying diseases.

Methods
Retrospective analysis of adult inpatient PJP cases (2014-2023). Diagnosis was presumptive (epidemiological, clinical, and imaging findings), or confirmed microbiologically. Statistical analysis utilized the chi-square test.

Results
Forty-two patients were identified: 66% male, median age of 47.5 years [25-83]. Seventy-four percent were HIV positive, with a median CD4+ count of 35 [1-347]. All had detectable HIV viral load, except one (suppressed for years, but with a new diagnosis of neoplasm). Non-HIV patients (26%) underlying diseases included hematological (n=6) or solid-organ malignancies (n=1), autoimmune diseases under corticosteroid therapy (n=2), pulmonary interstitial disease (n=1), and granulomatous systemic disease under investigation (n=1). Eighty-six percent had peripheral lymphopenia at diagnosis, and only one patient was receiving regular prophylaxis. The incidence of non-HIV patients significantly increased in the latter 5 years (5.5% vs 42%, p=0.008). Diagnosis was confirmed by positive direct antibody fluorescence staining in half of the patients. No molecular biology techniques or B-D-glucan assays were available. Seventeen (40%) patients required admission to level II or III units, of which 23% required invasive mechanical ventilation and 35% high-flow oxygen. Treatment included cotrimoxazole (n=40) and atovaquone (n=2). One-third of patients had cytomegalovirus reactivation, requiring antiviral therapy. Non-HIV patient mortality was significantly higher than HIV patients (45% vs 13%, p=0.023). Fifteen percent of survivors were readmitted within 30 days.

Conclusion
The epidemiology of PJP is evolving, with a noticeable increase in non-HIV cases, which are associated with significantly higher mortality despite appropriate treatment. Authors emphasize the importance of identifying new risk groups for chemoprophylaxis to improve prognosis.

Disclosures
All Authors: No reported disclosures
P-1054. BTK drives neutrophil activation for sterilizing antifungal immunity
Authors: Zarakas Marissa Agathonia , Desai Jigar , Wishart Andrew , Cunha Cristina , Carvalho Agostinho , Hohl Tobias M , Lionakis Michail S 
Published: January 2025

Abstract

Background
Bruton’s tyrosine kinase (BTK) is a critical component of B-cell receptor signaling and regulates B-cell proliferation and survival. Ibrutinib is an irreversible inhibitor of BTK and is successfully used in treatment of various B-cell malignancies. However, it has been associated with increased risk for invasive aspergillosis (IA).
Model of BTK-dependent responses promoting neutrophil activation in response to Aspergillus fumigatus.

Methods
To shed light in the susceptibility of ibrutinib-treated patients, we studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, BTKi-treated patients, and X-linked agammaglobulinemia patients.

Results
In response to fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and FcγR-dependent manner, leading to oxidative burst. BTK inhibition selectively impaired neutrophils’ capacity to damage Aspergillus hyphae, release primary granules and induce oxidative burst by impeding the activation of NADPH oxidase subunit p40phox and GTPase RAC2. Similarly, we found impaired neutrophil function in Aspergillus-infected, neutrophil-specific Btk deficient mice, whereas neutrophil recruitment and survival were spared. These defects were partially mitigated by GM-CSF via enhancing p47phox activation, supporting a role for GM-CSF use in susceptible patients. The presence of the BTK rs5951308 (T &gt;C; E24G) in donors of allogeneic hematopoietic transplant recipients was independently associated with increased risk of IA.

Conclusion
Our data uncover a previously unappreciated role for BTK in fungal immune surveillance against Aspergillus fumigatus.

Disclosures
All Authors: No reported disclosures
P-1062. In vitro Activity of Gepotidacin and Comparator Agents against a Collection of K. pneumoniae Urine Isolates from the United States During 2019-2022
Authors: Ryan Arends S J , Kapoor Renuka , Torumkuney Didem , Mendes Rodrigo E 
Published: January 2025

Abstract

Background
Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a unique mechanism of action, a distinct binding site and provides well-balanced inhibition (for most uUTI uropathogens) of two different type II topoisomerase enzymes. This study reports on the in vitro activity of gepotidacin and other oral antibiotics tested against contemporary Klebsiella pneumoniae clinical isolates collected from patients with urinary tract infections (UTI) in the United States as part of a gepotidacin global uropathogen surveillance study.

Methods
A total of 2,001 K. pneumoniae isolates were collected during 2019-2022 from 73 medical centres located in the United States. All isolates were tested for susceptibility by CLSI methods at a central laboratory (Element Iowa City). MIC results for comparator agents were interpreted per CLSI guidelines. MIC results for oral antibiotics approved for the treatment of uncomplicated UTI. Multidrug-resistant (MDR) and extended-spectrum β-lactamase (ESBL) subsets were interpreted per CLSI criteria.

Results
Gepotidacin (MIC50/90, 4/16 mg/L) displayed activity against 2,001 K. pneumoniae isolates (Table), with 94.9% of all observed gepotidacin MICs ≤ 16 mg/L. Susceptibility rates of oral comparators tested were ≤ 90.0% for amoxicillin-clavulanic acid (90.0%, MIC50/90, 2/8 mg/L), ciprofloxacin (86.3%, MIC50/90, 0.015/0.5 mg/L), levofloxacin (88.3%, MIC50/90, 0.06/1 mg/L), nitrofurantoin (34.0%, MIC50/90, 64/ &gt; 128 mg/L), and trimethoprim-sulfamethoxazole (84.7%, MIC50/90, ≤ 0.12/ &gt; 4 mg/L) (Table). Gepotidacin remained active against the 11.0% and 6.8% of K. pneumoniae isolates that displayed ESBL and MDR phenotypes, respectively, with observed MIC50/90 values of 8/32 mg/L for both.

Conclusion
Gepotidacin demonstrated potent in vitro activity against contemporary K. pneumoniae, including ESBL-producing and MDR isolates. Almost all oral comparator agents reported against US K. pneumoniae UTI isolates had susceptibility rates between 80-90% while the observed nitrofurantoin susceptibility rates were 34.0%, respectively.

Disclosures
Renuka Kapoor, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Didem Torumkuney, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Rodrigo E. Mendes, PhD, GSK: Grant/Research Support
P-1068. Inhibitory Effect of EDTA on Metallo β-Lactamase Producing Gram-Negative Pathogens Recovered from Cancer Patients with Bloodstream Infections
Authors: Raad Issam I , Rosenblatt Joel , Truong Y Lan , Gerges Bahgat Z , Jiang Ying 
Published: January 2025

Abstract

Background
The spread of metallo β-lactamase (Mβ-L) producing Gram negative pathogens is an important worldwide medical problem. It presents the broadest-spectrum β-lactam resistance of all carbapenemase-producing organisms leaving few remaining treatment options. Previously, adding EDTA, a potent metallo-chelator, was shown to restore activity for antibiotic combinations against Mβ-L pathogens isolated from patients with urinary tract and bronchial infections. In this study, we evaluated in vitro efficacy of EDTA alone and in combination with different β-lactam/β-lactamase inhibitors against Mβ-L isolates recovered from cancer patients with bloodstream infections (BSIs).

Methods
: EDTA over its concentration range was tested alone and in combination with cefepime (FEP)/Avibactam (AVI), and FEP/Tazobactam (TAZ) against ten Mβ-L blood clinical isolates {E.coli (n=6), K. oxytoca (n=2), P. aeruginosa (n=1), and E. cloacae (n=1)}. CLSI approved broth microdilution methods were used to measure MIC. MIC50, MIC90, MIC ranges, and susceptibility rate calculations were made according to CLSI 2022. The provisional breakpoints susceptibilities of FEP/AVI, FEP/AVI/EDTA are ≤8/4 while the provisional breakpoints for FEP/TAZ, and FEP/TAZ /EDTA are =≤2/4. Statistically, significant differences were determined using Fisher’s exact test (P≤0.05 is considered significant).

Results
Table 1. presents MIC50, MIC90, MIC ranges, susceptibility rates, and P values comparing EDTA with different concentrations alone and in combination with a range of FEP/AVI, and FEP/TAZ dilutions against ten Mβ-L bloodstream isolates.

Conclusion
EDTA alone at 100 mg/L, and 300 mg/L concentrations inhibited 100% of Mβ-L blood isolates, while 10 mg/L, and 50 mg/L inhibited 10%, and 90% of tested isolates respectively. The combination of 10 mg/L EDTA with FEP/AVI, and FEP/TAZ, synergistically improved the susceptibility rates from only10% (without EDTA) to 100% (at only10 mg/L EDTA). The differences in MICs, and susceptibility rates between the triple and double combinations were highly significant (P &lt; 0.0001). Further studies are needed to show the synergy against a larger number of Mβ-L Gram negative BSI pathogens as well as to clinically verify these benefits.

Disclosures
All Authors: No reported disclosures
P-1072. Evaluation of the Spontaneous Mutation Frequencies of SPR719 Alone and in Combination with Other Agents Used to Treat Mycobacterium avium Complex Pulmonary Disease
Authors: Pillar Chris , Walser Olivia , DeLaet Naomi , Leer Zach , Thwaites Mary , Hufnagel David A , Cotroneo Nicole , Critchley Ian A , Hamed Kamal 
Published: January 2025

Abstract

Background
SPR720 (fobrepodacin), a novel oral benzimidazole prodrug that inhibits the ATPase activity of mycobacterial DNA gyrase B, is being developed for treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD). SPR719, the active moiety of SPR720, has previously demonstrated antimycobacterial activity against nontuberculous mycobacteria (NTM), including Mycobacterium avium complex (MAC), the most common causative agent of NTM-PD.

Methods
In this study, the spontaneous mutation frequencies (SMFs) of MAC ATCC 700898 (macrolide-susceptible) and a clinical macrolide-resistant MAC isolate (MMX 9461) were evaluated in the presence of SPR719 alone, standard-of-care antimycobacterial agents (clarithromycin, ethambutol, and rifampin) alone, and for SPR719 in combination with these agents. The minimal inhibitory concentrations (MICs) for SPR719 and comparators against the NTM were determined by agar dilution. SMFs were determined by plating a high inoculum (108-109 colony forming units) on selective agar prepared at 2-, 4-, and 8-fold the MIC for SPR719, and at 4-fold the MIC for comparator agents. SMFs were also determined for SPR719 in combination with antimycobacterial agents where SPR719 was evaluated at 2-fold the MIC and a paired agent was evaluated at 4-fold the MIC. Putative mutants were patched from selection plates onto agar containing the selection drug, and susceptibility was then evaluated by broth microdilution alongside the parent isolate.

Results
All concentrations of SPR719 alone and in combination with other agents prevented growth of both isolates, resulting in low SMFs for SPR719 (&lt; 2.21 × 10-9 and &lt; 7.14 × 10-11). In contrast, mutants were readily selected with rifampin (SMF of 2.55 × 10-8 and 1.99 × 10-8) and clarithromycin (SMF of 1.16 × 10-8), and these mutants exhibited elevated MIC values ≥ 4-fold the MIC of the parent by broth microdilution. Colonies emerged during selection with ethambutol but were unstable and did not grow when patched onto ethambutol-containing agar.

Conclusion
The low propensity for the development of resistance against the novel agent SPR719 alone and in combination with other agents is important because emergence of resistance is a clinical concern in the setting of prolonged combination therapy for NTM-PD.

Disclosures
Nicole Cotroneo, B.S., Spero: Advisor/Consultant Ian A. Critchley, PhD, Spero: Employee Kamal Hamed, MD, MPH, Spero: Employee