bluuebunny/crossref_metadata_2025_split huggingface dataset:
2154. Cross-resistance of Ceftolozane-Tazobactam and Imipenem-Relebactam Against Clinical P. aeruginosa Isolates from Bloodstream and Respiratory Tract Infections– SMART United States 2019-2021
Authors: Lob Sibylle , Wise Mark G , Bauer Karri , Siddiqui Fakhar , Hilbert David W , Esterly John , DeRyke C Andrew , Young Katherine , Motyl Mary , Sahm Daniel F 
Published: November 2023

Abstract

Background
Antimicrobial resistance among Pseudomonas aeruginosa is challenging with limited treatment options. Ceftolozane/tazobactam (C/T) maintains activity against P. aeruginosa resistant to commonly used β-lactams. Imipenem/relebactam (IMI/REL) can restore the activity of IMI against P. aeruginosa. C/T and IMI/REL can be affected by different mechanisms of resistance, and pathogens can be nonsusceptible to one agent but susceptible to the other. We evaluated the activity of C/T and IMI/REL against P. aeruginosa isolates collected from patients with lower respiratory tract (LRTI) and bloodstream (BSI) infections in the United States as part of the global SMART surveillance program.

Methods
In 2019-2021, 24 US clinical labs collected up to 100 consecutive, aerobic or facultative, gram-negative pathogens from LRTI and up to 50 from BSI. Of 8643 collected isolates, 1986 (23%) were P. aeruginosa. Susceptibility was determined with CLSI broth microdilution and 2023 CLSI breakpoints.

Results
Among P. aeruginosa BSI and LRTI isolates, 88% were susceptible (S) to both C/T and IMI/REL, 2% were nonsusceptible (NS) to both agents; 8% were S to C/T but not to IMI/REL, and 2% were S to IMI/REL but not to C/T (Table 1). Among MDR and DTR isolates, 45% and 29%, respectively, were S to both C/T and IMI/REL and 11% and 20%, respectively, were NS to both. Among C/T-NS isolates, 57.3% and 44.0% were S to IMI/REL and ceftazidime/avibactam (CZA), respectively (Table 2). Among IMI/REL-NS isolates, 83% were C/T-S, 69% CZA-S, and &lt; 43% were S to all other studied β-lactams and LVX. Among CZA-R isolates, 61% and 47% remained S to C/T and IMI/REL, respectively.

Conclusion
Resistance to both C/T and IMI/REL was not common among recent clinical isolates of P. aeruginosa from the US, and both agents represent important treatment options. A significant proportion of isolates NS to one agent were S to the other, especially among MDR and DTR isolates. The data suggest that susceptibility to both agents should be tested.

Disclosures
Sibylle Lob, MD, Merck & Co., Inc.: Honoraria Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Fakhar Siddiqui, MD, MBA, Merck & Co Inc.: Employee Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
2161. Biofilm and Aggregate Formation as an Efficient Strategy Used by C. parapsilosis to Persist Echinocandin Treatment and Evade the Innate Immune Cells
Authors: Daneshnia Farnaz , Floyd Daniel , Hilmioğlu-Polat Süleyha , Ilkit Macit , Carvalho Agostinho , Munro Carol , Perlin David , Gabaldon Toni , Nobile Clarissa , Arastehfar Amir , Mansour Michael 
Published: November 2023

Abstract

Background
Biofilm and aggregate formation are thought to be critical strategies employed by fungal pathogens, such as Candida auris and Candida parapsilosis, to effectively colonize biotic and abiotic surfaces as well as to cause clonal outbreaks. Herein, we identified an immunocompetent patient experiencing persistent candidemia due to C. parapsilosis while under micafungin treatment. Four C. parapsilosis isolates were collected during the course of treatment, the initial isolate from the central venous catheter and the latter isolates from blood samples. We aimed to investigate microbiological attributes leading to immune evasion and micafungin therapeutic failure.

Methods
Whole genome sequencing (WGS) was employed to assess the genetic relatedness of the isolates. Detailed biofilm and aggregate formations were evaluated using confocal microscopy and cell wall staining and scanning electron microscopy was employed to assess cell wall changes. Interaction with primary neutrophils and macrophages and fungal burden in various organs of mice systemically infected with our isolates was carried out to assess the fitness.

Results
Whole-genome sequencing found isolates clonal. Interestingly, the latter isolates formed larger aggregates and thicker biofilm and a high concentration of micafungin was less effective against their biofilm structures. Detailed cell wall analysis found a concomitant incremental increase in mannan and a lower β-glucan and chitin of the latter isolates. Additionally, the latter isolates were less effectively phagocytosed by primary human macrophages and neutrophils, and macrophages infected with the latter isolates secreted significantly lesser proinflammatory cytokines, including TNFα and IL1β. Finally, mice infected with the latter isolates had a significantly higher burden in the kidney, liver, and spleen when compared to the initial isolate. Genomic changes underlying such morphological changes are under investigation, which will be used for transformation and functional studies.

Conclusion
Altogether, our study highlights that under certain conditions biofilm and aggregate formations can be employed by C. parapsilosis to effectively persist echinocandin treatment and evade the immune system.

Disclosures
Michael Mansour, MD, PhD, Thermofisher: Grant/Research Support
2181. Avibactam Prevents the in vitro Development of Imipenem Resistance in non-Carbapenemase-Producing Klebsiella pneumoniae
Authors: Quesille-Villalobos Ana M , Bolivar Consuelo , Nicolai Juan José , Herrera Veronica , Martinez Jose R W , Quiroz Valeria , Dias Lorena , Alcalde-Rico Manuel , Rafael Araos , Garcia Patricia , Munita José M 
Published: November 2023

Abstract

Background
Carbapenem resistance (CR) in Klebsiella pneumoniae is most frequently mediated by the production of carbapenemases. However, non-carbapenemase-producing K. pneumoniae (non-CP-Kpn) have been well documented. Overexpression of narrow β-lactamases can play an important role in the development of CR in the absence of carbapenemases. Here, we investigated the role of avibactam, a potent β-lactamase inhibitor, in preventing the in vitro development of CR in a non-CP-Kpn.

Methods
We used SCL-1, a non-CP-Kpn strain recovered from the bloodstream of a patient that developed CR in vivo during treatment with imipenem (IMI). SCL-1 was exposed to serial passages of increasing concentrations of IMI alone [0.25-16 μg/mL] or in combination with avibactam (IMI-AVI) during 8 days. In the case of IMI-AVI, the concentration of AVI was fixed at 4 μg/mL. Evolution assays were performed in triplicate and considered 3 independent evolutionary lines (ELs). MICs at each time-point were measured to IMI and IMI-AVI by broth microdilution as per CLSI. Growth curves of SCL-1 and evolved strains were performed to assess fitness. The expression levels of narrow spectrum β-lactamases blaOXA-1,blaOXA-10, and of the ESBL blaCTX-M-15 were measured by RT-qPCR.

Results
In vitro exposure to IMI led to CR, with the MICs increasing from 0.5 μg/mL to 8 μg/mL in all 3 ELs. In contrast, all ELs exposed to IMI-AVI remained fully susceptible to IMI after 8 days, with a final MIC of 1 μg/mL. In addition, the MIC to IMI of the evolved, IMI-resistant strains, in the presence of AVI (4 μg/mL) dropped from 8 to 1 μg/mL. Growth curves revealed that IMI-resistant strains evolved in IMI alone exhibited a growth defect as compared to both SCL-1 and the susceptible strains evolved in IMI-AVI. Finally, compared to the SCL-1, the expression level of blaOXA-1 was significantly increased (p&lt; 0.05) in all evolved isolates that developed IMI resistance (MIC=8 μg/mL). No significant changes were observed in the expression of blaOXA-10 and blaCTX-M-15 (Figure 1).Figure 1.RT-qPCR analysis of β-lactamase gene transcript levels for SCL-1 and evolutive lines (A and B). Data shown are individual data points with mean±SD superimposed.

Conclusion
Our findings suggest that the addition of AVI can prevent the in vitro development of IMI resistance in non-CP-Kpn. Our results have important implications for the clinical use of AVI as a strategy to combat CR in non-CP-Kpn infections.

Disclosures
All Authors: No reported disclosures
2189. Colistin Heteroresistance in Enterobacter due to Base Heterozygosity at Certain phoPQ Locations
Authors: Wang Chengcheng , Feng Yu , Zong Zhiyong 
Published: November 2023

Abstract

Background
Enterobacter species are major nosocomial pathogens, and the clinical implications and mechanisms of colistin heteroresistance (CHR) in Enterobacter remain unclear.

Methods
We used the population analysis profile (PAP) assay to determine the presence of CHR in Enterobacter. To examine whether CHR leads to treatment failure, we conducted in vitro time-killing assays and in vivo assays using murine intra-abdominal infection models. To determine the genetic mechanism for the CHR phenotype, we conducted whole-genome sequencing and ultra-deep second-generation sequencing.
A schematic outline of methods and main results

Results
In this study, we found that 30% of Enterobacter clinical strains causing bloodstream infections at West China Hospital exhibited CHR, which was associated with treatment failure and fatal infections, as demonstrated by in vitro time-kill tests and in vivo mouse infection modeling. We identified base alterations in the phoP-phoQ gene as the main resistance mechanism in Enterobacter CHR and that this heterogeneity originated from colistin selection and base heterozygosity, as detected by ultra-deep second-generation sequencing. We also found that several different resistance subpopulations existed simultaneously in the same strain with different resistance mechanisms.
Time-kill experiments in Enterobacter isolates with CHR or susceptible to colistin
CHR strains lead to in vivo colistin treatment failure
Phenotypic and genomic study of a CHR strain

Conclusion
We presented evidence for "genetic heterogeneity" in Enterobacter CHR strains, which is consistent with "phenotypic heterogeneity" and genetically explains the unstable and transient HR. This provides important insights and a fresh perspective into the mechanisms and clinical implications of Enterobacter CHR and underscores the importance of deep sequencing, prompting the research of high-throughput microbial single-cell sequencing as a method for detecting "genetic heterogeneity."
Frequency of bases that mediate colistin resistance at the same locus of phoP-Q in the parental and resistant strains

Disclosures
All Authors: No reported disclosures
2193. Vancomycin AUC:MIC Monitoring: Transitioning Safely from Inpatient to Outpatient Monitoring via OPAT
Authors: Campion Maureen , Aprile Richard , Troy Samantha , Tsuchida Yuran , Vindenes Tine 
Published: November 2023

Abstract

Background
Due to the increased availability of AUC:MIC calculators and evidence showing limited benefit to troughs greater than 15 mcg/mL, the 2020 IDSA/ASHP consensus vancomycin therapeutic guideline recommends AUC:MIC monitoring for patients with severe MRSA infections. At Tufts Medical Center (TMC) in Boston, MA, patients receive vancomycin dosed by AUC:MIC for severe MRSA infections or requiring greater than two weeks of therapy. There is limited information on transitioning these patients to the outpatient setting. Obtaining two appropriately timed levels in the rehabilitation, home infusion or nursing home setting can be extremely challenging. Therefore, at TMC, a correlating trough range associated with an AUC:MIC of 400-600 was calculated based upon patient specific parameters. This trough range was communicated to the outpatient parenteral antimicrobial therapy (OPAT) team for monitoring outpatient, reducing the need to draw 2 levels within the same dosing interval. The purpose of this study was to identify issues associated with transitions of care with vancomycin AUC:MIC monitoring and to identify potential solutions.

Methods
This was a retrospective review of patients receiving vancomycin dosed by AUC:MIC from September 2021 through March 2022. Patients who continued vancomycin with AUC:MIC monitoring on discharge were evaluated for challenges associated with their therapy by the OPAT coordinator. Data was collected on comorbidities, readmission to the hospital within 90 days, levels drawn incorrectly, patient non-compliance, need for re-education, and adjustment of therapy based on cultures.

Results
Seventy-two (72) patients received vancomycin monitoring by AUC:MIC at TMC. Of these patients, forty-two (42) were discharged with OPAT services. Twenty-six (26) of patients received intravenous vancomycin and sixteen (16) were prescribed other antibiotics. Twenty (20) patients planned for at least four weeks of outpatient therapy. The results of the outcomes of patients on therapy are listed in Table 1.

Conclusion
Our small study demonstrates AUC:MIC monitoring can be done safely and effectively in the outpatient setting. An emphasis should be placed on the education of the outpatient providers.

Disclosures
Maureen Campion, PharmD, shinoigi: Speaker
2203. ‘I always feel like, somebody's watching me’--Multimodal Antimicrobial Stewardship Supports Antibiotic Prescribing for Common Infections within the UNC Health Virtual Practice
Authors: Marx Ashley H , Mavrogiorgos Nikolaos , Barzin Amir 
Published: November 2023

Abstract

Background
Telehealth presents a new setting for antimicrobial stewardship interventions. Retrospective, disease-state-specific antibiotic review may be an effective mode of analyzing data and providing feedback to prescribers. The purpose of this project was to determine if prescriber-specific and composite team feedback were effective in maintaining adherence to preferred antibiotic selection and duration.

Methods
In July 2022, multimodal educational materials were distributed to UNC Health Virtual Practice providers to promote the use of preferred antibiotics and the shortest effective durations for common infections.
Encounter notes during the study period (6/1/2022 - 4/30/2023) were searched to determine eligible encounters corresponding urinary tract infections (UTI), skin and soft tissue infections (SSTI), pneumonia, and sinusitis. Eligible encounters with linked prescriptions were analyzed to determine whether antibiotic selection(s) and duration of therapy matched clinic-established best practices. The proportion of prescriptions corresponding to best practice for each infection type was calculated for each visit type, and for each provider.
Feedback consisted of provider-specific memos from the medical director on antibiotic selection and duration; composite team performance was shared with team members at provider meetings and senior leadership in administrative reports.

Results
The frequency of included visits was: sinusitis (393, 88%), SSTI (25, 6%), UTI (16, 4%), and pneumonia (11, 3%). The proportion of antibiotics corresponding to a firstline agent for each visit type were high for each included infection (range 72.6-100%; Table 1). Adherence to recommended duration of therapy was variable (range 12.5-100%). Six of 14 total prescribers had visits audited in both quarters. Among those, 5 of 6 increased or maintained personal performance from quarters 1 and 2 (Table 2).

Conclusion
Education followed by quarterly prescriber-specific and team feedback was associated with high rates of adherence to prescription of preferred agents. Use of the shortest effective duration of therapy presents additional opportunity for improvement. Targeted interventions for sinusitis provide the greatest stewardship opportunity for the UNC Health Virtual Practice. .

Disclosures
All Authors: No reported disclosures
2215. Impact of a Pharmacy-Driven Penicillin Allergy De-Labeling Pilot Program in Pre-Operative Cardiothoracic and Spine Surgery Patients at a Quaternary Hospital
Authors: Crum Hannah , Gagnon Brandon , Gens Krista 
Published: November 2023

Abstract

Background
Studies suggest up to 95% of patients with a reported penicillin (PCN) allergy can tolerate PCNs. Documented PCN allergies are associated with increased risks including Clostridioides difficile infections (CDI) and surgical site infections (SSIs). The goal of this study is to evaluate the effect of a pharmacist-driven PCN allergy de-labeling pilot program on the use of pre-operative beta-lactam antibiotics in cardiothoracic (CT) and spine surgery patients with documented PCN allergies.

Methods
This single-center, quasi-experimental study included adult patients with a charted PCN allergy and admitted for CT or spine surgery in 2021 (control group) and in the 6 months after the intervention pilot began (intervention group, 10/2022 - 03/2023). The primary outcome was rate of beta-lactam use peri-operatively. Secondary outcomes include SSI rates within 30 days after the operation, readmission rates within 30 days, CDI within 30 days of procedure, and hospital length of stay. In the intervention group, qualifying patients were interviewed via phone to assess allergy history. Chart documentation and allergy modification were completed to help ensure optimal antibiotic therapy. Qualified patients were de-labeled or referred to an allergist for outpatient skin testing and/or oral challenge.

Results
There were 214 patients in the control group and 72 in the intervention group. 57 (79.2%) patients in the intervention group were able to complete the interview. A total of 19 patients were referred to an outpatient allergist, and 7 were de-labeled (5 from pharmacist interview alone, 2 after allergist testing). Cefazolin was used pre-operatively in 91 (42.5%) of the control group vs. 55 (76.4%) of the intervention group (p&lt; 0.001). There was no significant difference in SSI rate, 2.3% in the control group vs. 4.2% in the intervention group (p=0.286). No significant difference was noted in any other secondary outcomes except length of stay 3.65 days in the control group vs. 2.06 days in the intervention group (p = 0.0134).

Conclusion
The pharmacy-driven PCN allergy de-labeling pilot program in CT and spine surgery patients was associated with increased beta-lactam use. There was no significant difference in SSI rates; however, the study was underpowered to detect a difference.

Disclosures
All Authors: No reported disclosures
2220. High burden of antibiotic exposure in left ventricular assist device (LVAD) recipients: A call for enhanced antimicrobial stewardship
Authors: Moore William J , Kling Kendall , Zembower Teresa , Jirak Alison , Nonog Gretchen , Magliola Grace , Harap Rebecca S , Wilcox Jane , Pham Duc , Wu Tingqing , Byrd Heather , Stosor Valentina 
Published: November 2023

Abstract

Background
LVAD patients are at high-risk for complications including hospitalization and infection, resulting in increased empiric use and lower thresholds for initiation of antibiotics (ABX). ABX utilization and risk for resistance development in this vulnerable patient population is not well established. We aimed to describe ABX exposure targeting early healthcare-associated infections (HAI) that occur in a complex patient population.

Methods
This was a review of ABX use among a prospective cohort of patients with recent LVAD to assess antibiotic burden. Study patients are being followed longitudinally to assess microbiota changes that occur with duration of LVAD support, development of any LVAD-related and unrelated infection, and ABX exposure. Included patients were enrolled from 7/2022 to 3/2023. World Health Organization’s AWaRe criteria, which groups agents based on potential for resistance development and need for stewardship prioritization, was used to classify antibiotic use. Summary and descriptive statistics were performed.

Results
Seventeen LVAD recipients were included with 53% having reported infection, totaling 21 distinct HAI. Infection types and antibiotic burden, including spectrum and duration are provided in Figure 1, with leading infection sites including respiratory (n=8), intra-abdominal (n=3), urine (n=3), and bloodstream (n=3). ABX courses exceeded most recommended durations, with a median of 11 days (IQR 8-16). Majority of episodes resulted in receipt of broad-spectrum antibiotics, including meropenem (n=7), piperacillin-tazobactam (n=6), and cefepime (n=4), despite limited occurrence of pathogens requiring these agents, Enterobacter spp (n=2), Pseudomonas aeruginosa (n=1). Observed ABX agents corresponded to WHO AWaRE Access (n=11.1%), Watch (n=83.3%), and Reserve (n=5.6%) groups, indicating frequent use of agents with high potential for resistance development.Figure 1.Antibiotic Burden & Infections following LVAD
Frequent use of broad-spectrum antimicrobials with high risk for resistance development observed in LVAD patients. WHO AWaRe criteria were used to identify higher risk agents, labeled as Watch and Reserve.

Conclusion
We found high rates of early HAI and broad-spectrum antibiotic use in patients with recent LVAD placement. These findings demonstrate potential opportunities for enhanced antimicrobial stewardship in this population to optimize therapy selection, mitigate risk of subsequent multidrug-resistant infections, and to preserve essential agents for future use.

Disclosures
Valentina Stosor, MD, DiaSorin S.p.A.: Advisor/Consultant|Eli Lilly & Company: Grant/Research Support
2231. Point Prevalence Survey on Antimicrobial Appropriateness in a Tertiary Care Hospital in Saudi Arabia
Authors: AlMahasnah Reem , AlQassim Hussain , AlQaysum Ibtihal , Atta Manal , AlRashidi Faris , Abufara Hanan , Hashhoush Mai , AlAjmi Noura , AlJishi Yamama 
Published: November 2023

Abstract

Background
Antimicrobial resistance is a significant global health problem. Optimizing the use of antimicrobial agents is a key strategic objective for any antimicrobial stewardship program (ASP). In the literature, 9-64% of antimicrobials prescriptions were inappropriate the hospital setting. We aim to evaluate antimicrobial utilization practices and subsequently implement informed interventions to optimize antimicrobial use by conducting a point prevalence survey (PPS).

Methods
This is a single-center PPS at King Fahad Specialist Hospital-Dammam, Saudi Arabia. The hospital is specialized in Transplant, Oncology/hematology, and Neuroscience, with approximately 350 beds. All inpatient wards were conducted over one week period ward by ward. All inpatients on active antimicrobials were included. Data were collected from patients’ electronic medical records based on the WHO methodology for PPS on antibiotic use in hospitals. The outcome (appropriateness of antimicrobial treatment) included five elements: indication, duration, administration route, spectrum, and dosing. Assessments were made according to the local and international guidelines and the ASP team (Infectious diseases consultant and pharmacist).

Results
A total of 316 patients’ medical records were screened. Of whom 121 were included. Nineteen (16%) patients were pediatrics, and 102 (84%) were adults. Patients’ characteristics are presented in Table 1. A total of 207 systemic antimicrobials were recorded, 117/207 (57%) therapeutic and 90/207 (43%) prophylactic. The antimicrobials were inappropriate in 73 /207 (35%) antimicrobial orders that included 84 elements. Eleven out of the 73 orders have more than one inappropriate element. The main reasons were inappropriate indication 31/84 (37%), followed by the antimicrobial spectrum 21/84 (25%). Figure 1Table 1:Characteristics of patients receiving systemic antimicrobial treatment, n (%)Figure 1:Elements of antimicrobials inappropriateness

Conclusion
This point prevalence survey showed 35% of the antimicrobial prescription in the inpatient setting was inappropriate. The most common reasons were the indication followed by the spectrum and duration of antimicrobials. These findings provide valuable insight into stewardship's best approach and interventions to improve antimicrobials appropriateness.

Disclosures
All Authors: No reported disclosures