bluuebunny/crossref_metadata_2025 huggingface dataset:
2896. Oral PrEP Uptake among HVTN 704/HPTN 085 Participants: Implications for the Future of Biomedical HIV Prevention Trials
Authors: Cantos Valeria D , Neradilek Moni , Gillespie Kevin , Huang Yunda , deCamp Allan C , Karuna Shelly T , Edupuganti Srilatha , del Rio Carlos , Veloso Valdilea , Cohen Myron S , Donnell Deborah J , Corey Lawrence , Roxby Alison C , Kelley Colleen F
Published: November 2023

Background

The HVTN 704/HPTN 085 clinical trial (AMP study) assessed the efficacy of VRC01 broadly neutralizing antibody infusions for HIV prevention. It offered access to oral pre-exposure prophylaxis (PrEP) at no-cost to all participants as standard of HIV prevention care. Understanding PrEP initiation among trial participants and describing its impact on study endpoints can guide future HIV prevention trial design.

Methods

We characterized sociodemographic and geographic features of PrEP initiation (by self-report) using descriptive statistics. We used Cox models to identify factors associated with PrEP initiation and the association between PrEP initiation (as a time-dependent exposure) and HIV incidence.

Results

Of 2221 participants off PrEP at enrollment, 31.8% initiated PrEP during the trial. Median time to PrEP initiation was 60 days (range 1-673 days). Brazil had the highest proportion of PrEP initiation among their enrolled participants (83.2%) and Peru had the lowest (5.3%). In US sites, 54.2% initiated PrEP. Southern US sites had the highest proportion of PrEP initiation (68.8%) and the Midwest had the lowest (28.4%).

In multivariate analysis, prior PrEP use [HR (95% CI) = 2.2 (1.3-4.0)] was associated with PrEP initiation. Participants from Switzerland [0.5 (0.3-1.0)] and Peru [0.08 (0.06-0.1)] had lower likelihood of PrEP initiation compared to the US, while participants from Brazil had higher likelihood [2.6 (2.0-3.3)]. Age, race, gender, and sexual orientation were not associated with PrEP initiation. HIV incidence rate was 3.6/100 person-years (PY) before PrEP initiation, compared to 1.2/100 PY after PrEP initiation. PrEP initiators had 58% less risk of acquiring HIV after adjusting for behavioral risk score and treatment arm. In the US, higher local PrEP-to-need ratio was also associated with lower PrEP initiation [0.9 per 5 units (0.8-1.0)].

Conclusion

Providing PrEP access to AMP participants reduced HIV acquisition among PrEP initiators. Study endpoints were still met due to heterogenous regional PrEP uptake and lower PrEP effectiveness than expected. These data suggest that offering oral PrEP to HIV prevention trial participants as standard of care is a feasible option to consider for future efficacy HIV prevention trial design.

Disclosures

Valeria D. Cantos, MD, Gilead Sciences: Grant/Research Support Srilatha Edupuganti, MD MPH FIDSA, Sanofi: Grant/Research Support Colleen F. Kelley, MD, MPH, Gilead Sciences: Grant/Research Support|Humanigen: Grant/Research Support|Moderna, Inc.: Grant/Research Support|Novavax, Inc: Grant/Research Support|Viiv Healthcare: Grant/Research Support
1854. Legionnaires’ Disease Case Exposure Classification Differs by Race and Ethnicity and Neighborhood Health — California, 2011–2021
Authors: Schember Cassandra O , Rutschmann Sarah , Kimura Akiko , Nguyen Alyssa , Vugia Duc , Jain Seema
Published: November 2023

Background

Legionnaires’ disease (LD) is a severe pneumonia caused by Legionella bacteria transmitted by inhalation of contaminated water droplets found in poorly maintained water systems. During 2012–2020, 53% of California LD patients were white and 14% were black; however, these groups account for only 39% and 6% of the population, respectively. Healthy Places Index (HPI) measures census tract health, which can affect risk for LD, by combining 23 indicators of social and environmental conditions. We assessed associations between race/ethnicity and neighborhood health, with LD case exposure classifications to establish priorities for decreasing LD disparities in California.

Methods

Using all California LD cases reported during 2011–2021 and six, individual modified Poisson regression models, we estimated incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for associations between race/ethnicity and neighborhood health (using HPI quartile) with three LD case exposure classifications (sporadic, healthcare-associated, or travel-associated). The most advantaged HPI quartile and non-Hispanic white race/ethnicity were the referent groups. All models controlled for birth sex, age, and year.

Results

Among 4,373 people with LD, 47% were white, 22% were Hispanic, 12% were black, and 22%–28% fell in each HPI quartile. Among cases, 78% were sporadic, 16% were travel-associated, and 5% were healthcare-associated. Black (IRR: 0.69; 95% CI: 0.55, 0.87) and Hispanic (IRR: 0.64; 95% CI: 0.52, 0.77) race/ethnicity were associated with decreased rates of travel-associated LD. Black (IRR: 1.06; 95% CI: 1.01, 1.11) and Hispanic (IRR: 1.11; 95% CI: 1.07, 1.16) race/ethnicity, and living in the least advantaged quartile (IRR: 1.05; 95% CI: 1.01, 1.10) were associated with increased rates of sporadic LD. Healthcare-associated LD was not associated with race/ethnicity or HPI.

Conclusion

We found evidence of racial and neighborhood disparities in sporadic LD, racial disparities in travel-associated LD, and no evidence of disparities in healthcare-associated LD. Efforts to increase uptake of water management programs in buildings in disadvantaged neighborhoods and travel accommodations might lessen LD burden and disparities in California.

Disclosures

All Authors: No reported disclosures
1863. Pediatric Nontuberculous Mycobacteria (NTM) Lymphadenitis: an Evolving Epidemiological Pattern in Northeast Ohio
Authors: Ackerman Aaron , Desai Ankita P , Shah Jay , Gropler Matthew
Published: November 2023

Background

This study describes the changing pattern of non-tuberculous, or atypical, mycobacteria (NTM) lymphadenitis over the past five years in Northeast Ohio and analyzes factors that may be associated with this change. Particular attention will be paid to any demographic or geographic associations that can be linked with this pattern, to assess for any changing epidemiology.

Methods

A retrospective chart review was completed including patients presenting to our tertiary medical center over the past five years. Patients with clinical presentation of lymphadenitis in the context of laboratory documented nontuberculous mycobacterial infection, or presumed infection, were included in the review.

Results

Thirteen patients with NTM lymphadenitis presenting in Northeast Ohio were identified during the five years from 2017 to 2022. Three patients (23.1%) presented between 2017 and 2019, while ten patients (77%) presented between 2020 and 2022. The median age on presentation was 16 months old (range of 12 to 40 months). Six were male (46.2%) and seven were female (53.8%). Nine (69.2%) had positive wound cultures for Mycobacterium avium complex (MAC) and four (30.8%) were managed presumptively. Four (30.8%) were managed with medication alone, four (30.8%) were managed with surgical excision alone, and five (38.5%) were managed with both medication and surgical excision. Seven (53.8%) were treated with rifampin and azithromycin, one was treated with clarithromycin and rifabutin, and one was treated with azithromycin and ethambutol. Eight (61.5%) underwent surgical excision. Five (38%) lived within 4 miles of Lake Erie and 8 (62%) lived within 7.5 miles of Lake Erie.

Conclusion

Thirteen cases of NTM lymphadenitis were identified over a five-year period in Northeast Ohio. The incidence increased from the years 2017-2019 (23.1%, n=3) to 2020-2022 (77%, n=10). Of the patients, 30.8% (n=4) responded to medication alone and 30.8% (n=4) responded to surgical excision alone, with 38.5% (n=5) requiring both medication and surgical excision. Medical therapy included combination therapy with macrolide in all cases. It is unclear if the geographic proximity to Lake Erie is contributing to the cases of NTM lymphadenitis in our area, but this needs to be further elucidated.

Disclosures

All Authors: No reported disclosures
1880. Comparative Analysis Between Elderly And Non-Elderly Tuberculosis Patients
Authors: Hammami Fatma , Koubaa Makram , Rekik Khaoula , Chakroun Amal , Smaoui Fatma , Marrakchi Chakib , Jemaa Mounir Ben
Published: November 2023

Background

Tuberculosis (TB) remain a public health issue worldwide. All ages might be involved. With the rise of the elderly population, which is more susceptible to TB disease, an increase of TB among this age group is reported. We aimed to compare clinical features and treatment outcomes between elderly and non-elderly TB patients.

Methods

We conducted a retrospective study including all patients hospitalized in the infectious disease department for extrapulmonary TB between 1990 and 2022. Patients aged ≥ 60 years were considered as elderly TB patients.

Results

We encountered 488 non-elderly patients (79%) and 130 elderly patients (21%). Previous medical history of personnel TB (13.8% vs 6.6% ; p=0.007), cancer (10.8% vs 3.7% ; p=0.001) and diabetes mellitus (13.8% vs 3.3% ; p< 0.001) were significantly more frequent among the elderly group. Fever (55.4% vs 54.1% ; p=0.794), loss of appetite (49.2% vs 43.1% ; p =0.213), weight loss (38.5% vs 41% ; p=0.603) and night sweats (33.8% vs 30.8% ; p=0.506) were the revaling symptoms among elderly and non-elderly group. Osteoarticular TB (24.6% vs 11.3% ; p< 0.001) and urogenital TB (20% vs 8.4% ; p< 0.001) were significantly more frequent among the elderly group. Lymph node TB was significantly less frequent among the elderly group (37.7% vs 50.9% ; p=0.007). The elderly patients received separate tablets of antitubercular therapy more frequently (63.1% vs 49.8% ; p=0.007). Side effects of treatment were reported among the elderly (30.8%) and the non-elderly (34.6%), with no significant difference (p=0.408). Complications (22.3% vs 19.3% ; p=0.440), sequelae (13.8% vs 11.9% ; p=0.545), relapse (1.5% vs 4.5% ; p =0.119) and death (2.3% vs 1.8% ; p=0.723) were noted among elderly and non-elderly group, with no significant difference.

Conclusion

Although the elderly had more comorbidities, the revealing symptoms and the disease evolution of extrapulmonary TB were similar in comparaison with the non-elderly patients. Osteoarticular and urogenital TB were more frequent among the elderly. Strategies to maintain a close follow-up and adequate social support are maindatory in order to garantee a favorable evolution of TB.

Disclosures

All Authors: No reported disclosures
1883. Features and Outcomes of Tuberculosis in Documented versus Undocumented Migrants in Israel
Authors: Zohar Iris , Pomeranz Adam , Harari Orna Schwartz , Ben-David Debby , Maor Yasmin
Published: November 2023

Background

In countries with low tuberculosis (TB) incidence, most TB cases are observed in foreign-born individuals, including permanent immigrants, and undocumented migrants. There is limited information regarding the differences within these groups. In Israel, where TB prevalence is < 2 cases/100,000 persons, 85% of TB cases occur in foreign-born people. We examined risk factors, clinical course, and outcomes between documented and undocumented immigrants hospitalized with active TB.

Methods

A retrospective analysis of medical records from foreign-born active TB patients admitted to a 700-bed hospital in the center of Israel between January 1st, 2019, to March 31st, 2023. We included patients who initiated TB treatment during hospitalization and were discharged by April 2023. Undocumented migrants were defined as non-Israeli citizens without medical insurance. We summarized their clinical characteristics, course, and outcomes.

Results

48 patients were included, 21 (43.8%) were undocumented migrants. Undocumented migrants were younger (mean age 40.9 vs. 53.0 years, P< 0.001) and predominantly arrived from Africa (95.2% vs. 29.6%, P< 0.001). The prevalence of HIV was similar between both groups. Presenting symptoms, duration of symptoms before admission, rates of bilateral and cavitary pulmonary disease, and extrapulmonary disease were comparable. Multi-drug resistant TB was rare (0% vs. 11.5%, P=0.242). Among patients with positive sputum smears and follow-up, undocumented migrants experienced a longer time to achieve negative sputum cultures (76.0 days vs. 36.8 days, P=0.004), and hospitalizations lasting over 30 days were also more common among undocumented migrants (71.4% vs. 40.7%, P=0.045). Multivariate analysis identified undocumented migrant status, thrombocytosis, and bilateral and cavitary pulmonary disease as risk factors for prolonged hospitalization.

Conclusion

Although the clinical features of TB were similar between documented and undocumented migrants, the response to treatment was slower, and hospital stays were longer among undocumented migrants. This may be due to undocumented migrants presenting with more advanced disease or lack of suitable conditions for isolation and treatment at home.

Disclosures

Yasmin Maor, MD, Astra Zeneca: Advisor/Consultant|Astra Zeneca: Honoraria|Gilead: Honoraria|GSK: Honoraria|kamada: Honoraria|Medison: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Pfizer: Grant/Research Support|Pfizer: Honoraria
1898. Optimizing selection of latent TB management strategies among immigrants from high TB burden settings to the United States
Authors: Sinha Pranay , Jacobson Karen R , Horsburgh C Robert , Linas Benjamin P , Acuña-Villaorduña Carlos
Published: November 2023

Background

Treatment for latent tuberculosis infection (LTBI) with rifampin and isoniazid is very effective but carries significant hepatotoxicity risks, increasing with age. Further, since the risk of progression to tuberculosis (TB) disease declines with increasing time from exposure, the risk is highest among recent immigrants. Current guidelines may therefore promote overtreatment of LTBI, particular in older immunocompetent individuals who immigrated many years previously.

Methods

Using observed data from the Boston Medical Center/Boston Public Health Commission TB clinic and best literature estimates, we designed a microsimulation model to simulate TB progression among immunocompetent adult immigrants from high TB burden countries without abnormal radiography, alcohol or tobacco use, or recent TB contacts over a 30-year horizon (Table 1). We assumed that the simulated individuals were exposed to TB immediately prior to immigration. TB progression rates are based on years since exposure (Table 1). We evaluated three strategies: 1. No treatment 2. Rifampin and 3. Isoniazid for new 35 years-old and 65 years-old immigrants and for 35 and 65 years-old immigrants who had immigrated 25 years previously. We simulated hepatotoxicity using published estimates (Table 2). The model calculates costs and outcomes (TB cases and disability-adjusted life years) associated with each strategy. We used deterministic and probabilistic sensitivity analyses to test robustness of our results.

Results

Among new immigrants both 35 and 65 years-old, rifampin provides better outcomes at lower cost than both the isoniazid and no treatment strategies (Table 3). Among those who immigrated 25 years ago, Rifampin remains the preferred strategy in 75% of simulations for 35 years-old individuals and no treatment was preferred in 100% of iterations for 65 years-old patients. For those unable to receive rifampin due to drug interactions, no treatment became the preferred strategy for a broader range of individuals (Figures 1a and 1b).

Conclusion

Age and time since immigration must be considered to determine whether LTBI therapy is indicated in immunocompetent immigrants from high TB burden countries. Our results could help clinicians optimize strategies for LTBI treatment and minimize harm.

Disclosures

All Authors: No reported disclosures
1901. High Prevalence of Latent Tuberculosis Infection in a Malaysian Prison
Authors: Zhang Lu , Shenoi Sheela , Kamarulzaman Adeeba , Dhaliwal Sangeeth , Ahmad Ahsan , Altice Frederick
Published: November 2023

Background

Given the rising tuberculosis (TB) incidence and mortality, strengthening the identification and treatment of those with latent tuberculosis infection (LTBI) is urgently needed. Prisons are a TB hotspot but there is a paucity of data on LTBI in prisons. This study characterized LTBI in the largest prison in Malaysia.

Methods

From 22nd October 2019 to 19th January 2023, adults newly admitted (< 2 days) to the Kajang men’s prison without current active TB (excluded by negative culture, Acid-Fast Bacillus smear, or GeneXpert results) or a history of active TB in the past 2 years, were invited to participate. Enrollees underwent tuberculin skin tests (TST), chest X-ray, and blood tests for HIV, hepatitis C (HCV), hepatitis B, and c-reactive protein (CRP). Sociodemographic variables and drug use history were collected by questionnaires. LTBI was defined as TST size ≥ 5mm for people living with HIV and ≥ 10mm for people living without HIV, without evidence of active TB. Multivariable logistic regression was performed to identify independent correlates of LTBI by stepwise backward regression with inclusive factors from univariate analysis (p< 0.1). Multicollinearity was checked by the variance inflation factor (VIF).

Results

We enrolled 601 eligible people deprived of liberty, with a median age of 42 (IQR 36-50), 8.8% living with HIV, 43.4% with HCV infection. The prevalence of LTBI was 68.2% (95%CI: 64.4%-71.8%). The independent risk factors for LTBI overall (Table 1) included opioid use disorder, history of homelessness, and HCV. Marijuana use was associated with decreased risk of LTBI among all cases and among people with HIV. For people without HIV, HCV and CRP≥ 5mg/ml were independent risk factors for LTBI, while methamphetamine use was associated with a reduced risk of LTBI.

Conclusion

The prevalence of LTBI in a Malaysian prison was high, necessitating the implementation of TB preventive therapy. The high prevalence of HCV may increase the risk of hepatotoxicity during LTBI treatment. Further data is needed on the risks of TB preventive therapy among people deprived of liberty.

Disclosures

All Authors: No reported disclosures
2902. Dalbavancin Use in Bone and Joint Infections
Authors: Sanikommu Srivani , Alderson Liam P , Bailey Brett , Stambough Jeffrey , Stronach Benjamin , Mears Simon , Dare Ryan K
Published: November 2023

Background

Dalbavancin (DAL) is currently FDA-approved to treat acute bacterial skin and soft tissue infections. Use of DAL for off-label indications have been reported in difficult-to-treat infections, including osteomyelitis and prosthetic joint infections. Once weekly DAL dosing is an attractive alternative to daily intravenous (IV) infusions decreasing risks of prolonged home IV therapy. However, effectiveness for treatment of bone and joint infections is unknown

Methods

This single-center, retrospective, observational study included adult patients who received at least one dose of DAL from 09/2019-03/2023 for bone and joint infections. Patient demographics including state and national area of deprivation index (ADI) data, underlying infection, dalbavancin indication, surgical and medical treatments, and clinical outcomes were obtained. Risk factor analyses were performed for 1-year infection recurrence using Stata 15.0 statistical software.

Results

Fifty-eight patients were treated with DAL with a mean age was 44.3 years, with males comprising 71% with a mean BMI of 28.6. This vulnerable patient population had an Arkansas ADI decile of 6.1 and a national ADI percentile of 81.2. Osteomyelitis (81%), prosthetic joint infections (PJIs) (10.3%,), and native joint infections (8.6%) were included. Twenty-five (43.1%) patients had infected hardware involved. The majority (86.2%) of patients underwent surgical debridement and 17 (29%) required hardware removal, leaving 8 (13.8%) with retained hardware. Staphylococcus aureus was the most common organism identified with 39.7% and 31.0% MRSA and MSSA respectively. The most common DAL indication was IV drug use (43%). Recurrence of infection occurred in 8 patients (13.7%) within 90 days and 10 patients (17.2%) at one year. Hardware retention was noted to be a significant risk factor for recurrence (p=0.024), and hardware removal decreased risk of recurrence (p= 0.026). There was no recurrence in PJIs and there were no deaths noted.

Conclusion

Our evidence suggests that DAL is an effective treatment option for bone and joint infections with debridement and hardware removal. Hardware retention increased risk for 1-year recurrence. Further evaluation with prospective, randomized controlled trials is needed.

Disclosures

All Authors: No reported disclosures
2128. In Vitro Activity of Ceftibuten-Avibactam and Comparator Agents Against Resistant Enterobacterales from UTIs Collected Globally as Part of the ATLAS Surveillance Program, 2022
Authors: Hackel Meredith , Stone Gregory , Sahm Daniel F
Published: November 2023

Background

Increasing resistance among agents commonly prescribed to treat urinary tract infections (UTIs) indicate that new orally bioavailable agents are needed. Ceftibuten (CTB) is an orally administered third-generation cephalosporin and is in early clinical development being combined with an oral prodrug of avibactam (AVI). AVI is a non-β-lactam inhibitor of Ambler class A β-lactamases, including ESBLs and KPCs, class C (AmpC) β-lactamases, and some class D (OXA-48) β-lactamases. Ceftibuten-avibactam prodrug (CBA) is in early clinical development as a potential oral treatment for complicated urinary tract infections. This study evaluated the in vitro activity of CBA and oral comparators against Enterobacterales from UTIs with drug-resistant phenotypes collected globally as part of the 2022 Antimicrobial Testing Leadership and Surveillance (ATLAS) program.

Methods

4,265 non-duplicate clinical isolates from UTIs were collected in 2022 in 55 countries. Susceptibility testing with CBA tested at a fixed concentration of 4 µg/mL AVI and comparators was performed by CLSI broth microdilution and interpreted using CLSI 2023 breakpoints. Nonsusceptible (NS)/resistant (R) phenotypes were based on 2023 CLSI breakpoints. MDR was defined as R to ≥1 agent from ≥3 drug classes.

Results

CBA was the most active compound tested against all Enterobacterales, with the MIC90 value decreasing from 32 µg/mL to 0.12 µg/mL. A total of 96% of all isolates were inhibited at a CBA MIC of ≤1 µg/mL. Percent susceptible of oral comparators ranged from 63.4% to 76.8%. CBA maintained activity against NS/R subsets of Enterobacterales (MIC90 range, 0.25 to 4 µg/mL; 85.0% to 93.2% inhibited at ≤1 µg/mL), including MDR isolates (MIC90, >64 µg/mL; 81.7% inhibited at ≤1 µg/mL).

Conclusion

Ceftibuten-avibactam demonstrated potent in vitro activity against multidrug-resistant Enterobacterales collected globally. Ceftibuten -avibactam prodrug could be an effective oral therapy for difficult-to-treat infections caused by multidrug-resistant Enterobacterales.

Disclosures

Meredith Hackel, PhD, Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Gregory Stone, PhD, Pfizer: Stocks/Bonds Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
2135. Epetraborole in vitro Activity Against Mycobacterium avium complex Recent Clinical Isolates from Japan
Authors: White Tiffany Keepers , Aono Akio , Igarashi Yuriko , Chikamatsu Kinuyo , Takaki Akiko , Mitarai Satoshi
Published: November 2023

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 and is currently under clinical development for treatment of treatment-refractory Mycobacterium avium complex (MAC) lung disease. The objective of this study was to evaluate the in vitro activity of EBO against recent MAC isolates from Japan.

Methods

Minimal inhibitory concentration (MIC) values for EBO, amikacin (AMK), clarithromycin (CLR), rifabutin (RFB), and ethambutol (EMB) were determined using broth microdilution assays according to Clinical and Laboratory Standards Institute M24-A3 guideline (2018) against 110 MAC clinical isolates collected from Japanese patients in 2020. MAC isolates were of respiratory origin and included 55 M. avium and 55 M. intracellulare isolates.

Results

EBO (MIC) values ranged from 0.25 - 16 µg/mL and the EBO MIC50 and MIC90 were 2 and 4 µg/mL, respectively (Table 1). The CLR MIC range was 0.125 - > 32 µg/mL and included 4 CLR-resistant isolates (MIC ≥ 32 µg/mL). CLR MIC50 and MIC90 were 1 and 4 µg/mL, respectively. All isolates were susceptible to AMK and had an MIC range of 2 - 32 µg/mL; the MIC50 and MIC90 were 8 and 16 µg/mL, respectively. The EMB MIC range was 2 - > 32 µg/mL; the MIC50 and MIC90 were 4 and 16 µg/mL, and the RFB MIC range was ≤0.03 - 2 µg/mL and MIC50 and MIC90 were 0.06 and 0.25 µg/mL. EBO maintained activity with MIC values of 0.25 - 2 µg/mL against the 4 CLR-resistant isolates.

Epetraborole and comparator antimicrobial minimum inhibitory concentration values against 110 recent Mycobacterium avium complex clinical isolates from Japan

MIC=minimal inhibitory concentration; MIC50=minimal inhibitory concentration for 50% of isolates tested; MIC90=minimal inhibitory concentration for 90% of isolates tested.

Conclusion

EBO demonstrated potent in vitro activity against 110 recent MAC isolates collected from Japanese patients. Furthermore, EBO demonstrated in vitro activity against CLR-resistant MAC isolates suggesting that CLR-resistance does not impact EBO activity. These data are similar to results obtained against U.S. isolates and support the continued clinical evaluation of the use of EBO in the treatment of MAC lung disease in Japan.

Disclosures

Tiffany Keepers White, PhD, AN2 Therapeutics: Employee|AN2 Therapeutics: Stocks/Bonds Satoshi Mitarai, MD, PhD, AN2 Therapeutics, Inc.: Grant/Research Support
2141. Preclinical Evaluation of PA-001: A Novel, Potential Macrocyclic Peptide-Based Treatment for COVID-19 Which Binds to the S2 Subunit of SARS-CoV-2 Spike Protein
Authors: Kawamura Tatsuro , Ohuchi Masaki , Nagasawa Takayuki , Ohashi Hirofumi , Iwata-Yoshikawa Naoko , Shiwa-Sudo Nozomi , Sakai Yusuke , Matsui Katsuma , Matsumoto Masatoshi , Kurasaki Haruaki , Nagatomo Kazutaka , Ito Shoko , Kawamura Naoki , Masuya Keiichi , Nagata Noriyo , Watashi Koichi , Suzuki Tadaki , Kitamura Hidetomo , Murakami Masato
Published: November 2023

Background

Despite the approval of a few COVID-19 drugs, various mutations of SARS-CoV-2 continue to emerge and pose as a threat to the efficacy of COVID-19 treatments. To address the unmet clinical need for broad-spectrum treatments, we identified and performed preclinical evaluation of PA-001, a macrocyclic peptide that targets the highly conserved S2 subunit (S2) of the spike protein of SARS-CoV-2, as a potential therapeutic agent with a new mechanism of action.

Methods

A diverse macrocyclic peptide library was constructed and screened for S2 binders employing PeptiDream’s proprietary technology, Peptide Discovery Platform System (PDPS). In vitro antiviral activity was evaluated in VeroE6/TMPRSS2 cells infected with SARS-CoV-2 using RT-qPCR. In vivo efficacy was evaluated in a lethal BALB/c mouse model infected with a mouse-adapted SARS-CoV-2 strain, QHmusX, where PA-001, the remdesivir metabolite GS-441524, alone or in combination, or molnupiravir were therapeutically administered for 3 consecutive days started at 1-day post-inoculation (Fig. 1).Figure 1.Schematic design of the in vivo efficacy study

Results

PA-001 was identified as a S2 binding peptide through PDPS. PA-001 showed in vitro antiviral activity against wild-type and variant strains of SARS-CoV-2 including Omicron (IC50: 1.7 – 9.6 nM). Therapeutic administration of PA-001 completely rescued mice from SARS-CoV-2-caused death at the anticipated clinical dose, while 80% of molnupiravir-administered mice died (Fig. 2A). In addition, treatment with PA-001 alone significantly suppressed body weight loss (Fig. 2B), decreased lung weight-to-body weight ratio (an indicator of lung inflammation), and reduced inflammatory cytokines secretion including IL-6 in lungs, and these effects were enhanced when combined with GS-441524.Figure 2.Survival rate and body weight change of SARS-CoV-2-infected mice

Conclusion

The S2-targeting peptide PA-001 showed potent in vitro antiviral activity and in vivo preclinical therapeutic efficacy. These data support the possibility that PA-001 could become a novel drug with a unique mechanism of action for the treatment of COVID-19. Currently, IND submission for PA-001 is in preparation to initiate clinical trials.

Disclosures

All Authors: No reported disclosures
2145. Antagonistic Activity of Lacticseibacillus rhamnosus R3 Against Carbapenem-Resistant Acinetobacter baumannii Strain: A Promising Therapeutic Alternative
Authors: Rodriguez Cecilia , Ramlaoui Dema , Georgeos Nardin , Gasca Briea , Leal Camila , Salzameda Nicholas , Bonomo Robert A , Raya Raul , Ramirez Maria Soledad
Published: November 2023

Background

Acinetobacter baumannii (AB) is a recognized nosocomial pathogen of critical importance Most circulating AB strains are carbapenem-resistant (CRAB), which severely complicates therapeutics with available antibiotics. Probiotic lactic acid bacteria constitute a promising therapeutic alternative. Previously, we determined that Lacticaseibacillus rhamnosus R3 (LR-R3) exerts a strong inhibitory capacity on the model strain A118 (susceptible to antibiotics). In this analysis, the antimicrobial activity of LR-R3 against type CRAB hypervirulent strain AB5075 was evaluated.

Figure 1

A) Transwell migration assay. AB5075 viability after 24h exposure to LR-R3 CFCM. B) CFCM activity obtained from 96h culture of LR-R3 on CRAB strains.

Methods

The inhibitory activity of cell pellet and its cell-free supernatants (CFCM) were determined, respectively, by the soft-agar overlay method, CFCM activity, and transwell migration assay. Also, killing assays and scanning microscopy imaging were performed under co-culture conditions. Lastly, AB5075 transcriptional response when exposed to LR-R3 was assessed by RT-qPCR.

Results

The lactic acid bacteria LR-R3 demonstrated a strong inhibitory capacity on AB5075 strain (inhibition halo diameter, DHI >20 mm), with loss of cell viability at 4h of co-culture conditions. The CFCM of LR-R3 also showed similar antimicrobial activity on AB5075 (Fig 1A) and against others CRAB strains (Fig 1B), suggesting that the inhibitory effect observed is due to the presence of a compound or metabolite produced and secreted by the lactobacillus.

Microscopy images showed increase formation of outer membrane vesicles (OMVs) and the presence of nanotubes. In addition, significant changes in the expression levels of the studied genes were observed in AB5075 in co-culture with LR-R3: increase in the expression of genes involved in biofilm (csuAB, csuB, ompA); and decrease in the expression of genes involved in the synthesis and utilization of iron (bauA, exbD, bfnA, basE, pirA), and genes related to fatty acid and lipid metabolism (paaA, paaB).

Conclusion

The results obtained allowed the identification of Lcb. rhamnosus R3 as a probiotic strain with antagonistic activity on the nosocomial pathogen A. baumannii. In addition, it was shown that LR-R3 alters iron and fatty acid metabolism, by virtue of this interaction. This work constitutes the basis for future studies necessary to elucidate the mechanism involved.

Disclosures

Robert A. bonomo, MD, Entasis, Merck, VenatoRx, Wockhardt: Grant/Research Support
2195. Impact of Optimizing Urine Culture Susceptibility Reports on Prescribing of Antimicrobials in Outpatients at the Atlanta VA Health Care System (AVAHCS)
Authors: Gale Christopher , Goolsby Tiffany , Webster Andrew S
Published: November 2023

Background

To encourage appropriate prescribing in uncomplicated urinary tract infections (UTIs), the AVAHCS optimized urine susceptibility reports by adding comments guiding selection of narrow-spectrum beta-lactams for Enterococcus spp and certain Enterobacterales (E. coli, K. pneumoniae, Proteus spp) and hiding the susceptibility of levofloxacin for Enterococcus spp. The purpose of this study is to determine the impact of these changes on antibiotic selection in outpatients.

Methods

This study was a retrospective chart review of patients with positive urine cultures for the target organisms from March - December 2019 and March - December 2022. Patients were included if they had urine cultures that resulted with one of the target organisms and received UTI treatment. Those excluded had positive blood cultures or were hospitalized at the time of sample collection, had a previous urine culture or received treatment for UTI within 30 days, had a urological procedure in the preceding 12 months, or had a polymicrobial culture result. The primary outcome was the percent change in the use of quinolones before and after implementation. Secondary outcomes included the percent change in the use of aminopenicillins and cephalosporins for Enterococcus spp and Enterobacterales, respectively.

Results

For Enterococcus spp, there was a 29.2% decrease in the selection of quinolones as definitive therapy. There was a 37.1% increase in the use of aminopenicillins as definitive therapy. For Enterobacterales, there was a 15% decrease in the selection of quinolones as definitive therapy. There was a 13.3% increase in the use of first-generation cephalosporins as definitive therapy.

Conclusion

For Enterococcus spp UTI, following suppression of levofloxacin from the C&S reports and addition of provider comments, quinolones were less likely to be prescribed and aminopenicillins were more likely to be prescribed. In Enterobacterales UTI, following addition of prescriber comments, quinolones were less likely to be prescribed and first-generation cephalosporins were more likely to be prescribed, though the increase was less pronounced than was seen in the Enterococcus spp group. These results suggest the combination of susceptibility suppression and comments was more impactful than a comment alone.

Disclosures

All Authors: No reported disclosures
2200. The Antibiotic Steward's Nightmare: Long-Term Antibiotics in An Infectious Disease Practice
Authors: Karkenny Gabriel , Pao Megan , Demissie Seleshi , Shah Nikeith , Hirsch Bruce
Published: November 2023

Background

The effects of long-term antibiotic use, including the frequency of recurrent infections and new-onset resistant infections, are not fully understood. The role of antibiotics in the disruption of the gut microbiota has been well-described, impacting insulin susceptibility and lipid deposition.

Prolonged antibiotic use may have potential to be implicated in obesity, diabetes, and hyperlipidemia. There may also be an effect on the incidence of secondary infections with new organisms, the frequency of breakthrough infections from the index organism, and the selection for resistant infections.

Methods

This retrospective study evaluated 78 patients seen at an outpatient infectious disease practice. Inclusion criteria were patients with prescription of an oral antibiotic for 90 or more consecutive days between 9/1/18 and 12/31/2019, who utilize a health system pharmacy. Data was collected from patient charts at baseline prior to antibiotic initiation, and at time of most recent follow up after the initiation of antibiotic.

Results

Cephalexin (37.2%), azithromycin (34.6%) and amoxicillin (12.8%) were the most common antibiotics prescribed. Mean patient age was 69.4 years. Indications for antibiotic use included NTM infections (34.6% of cases), prosthetic joint infections (21.8%), recurrent UTIs (10.3%), and prosthetic valve infection (7.7%). 23.4% of patients experienced breakthrough infection with the index organism, while 21.8% experienced new, unrelated infection during follow-up, of which 52.9% had a resistant organism isolated. Mean BMI at baseline was 26.9, and BMI at follow-up was 27.3. The difference between baseline and follow-up BMI was not statistically significant (p=0.177). A1C, LDL, and cholesterol rose from baseline to follow-up, but did not reach statistical significance.

Conclusion

Patients on long-term antibiotics had a numerical increase in BMI, A1C, LDL, and cholesterol values following initiation, but those increases were not statistically significant. Recurrence of infection and emergence of resistance was common. The small sample size and limitation of studying patients from one practice within one health system pharmacy are limitations of the study. Further studies with larger sample sizes and comparative groups by diagnosis are needed.

Disclosures

All Authors: No reported disclosures
2202. Missed Opportunities for Penicillin Allergy De-labeling in Infectious Disease Clinics
Authors: Martinez-Palmer Meaghan , Khan Parisa F , Xu Teena
Published: November 2023

Background

90% of patients who report a penicillin allergy are not truly allergic and can safely receive penicillins. Patients labeled as “penicillin allergic” are more likely to receive non-beta lactam antibiotics and suffer worse clinical outcomes. In this study, we aimed to quantify the rate of missed opportunities for penicillin allergy de-labeling in patients seen in ID clinic.

Methods

This single-center retrospective study identified patients with a documented penicillin allergy who attended an ID clinic appointment between 1/1/21 and 12/31/22. Allergy history was ascertained by chart review. Extracted data included date of reaction entry into the medical record, reaction type (IgE-mediated, unknown reaction, side effect, severe cutaneous adverse reactions/non-IgE-mediated), observed or historical reaction, severity of reaction, and documented tolerance of penicillin since initial reaction. Patients who had tolerated penicillins since reaction or had side effects were eligible for immediate de-labeling. Patients with unknown reactions, remote IgE-mediated allergies >10 years ago, or non-severe IgE-mediated allergies >5 years ago were considered candidates for further evaluation and penicillin allergy testing. All other reactions were considered ineligible for further evaluation.

Results

Of the 83 patients reviewed, 54 had reactions suggestive of an IgE-mediated allergy (Figure 1). 99% of patients had historical, self-reported reactions. At the time of ID clinic visit, 31 patients were eligible for immediate de-labeling due to tolerance of penicillins since reaction. Only 4 patients were ineligible for further evaluation. Median duration of penicillin allergy label was 18.8 years. 12 patients were ultimately de-labeled by the time of chart review.

Figure 1

Types of Reactions

Conclusion

37% of patients with penicillin allergies seen in an ID clinic were eligible for immediate allergy de-labeling. These findings demonstrate a high rate of missed opportunities for ID providers to remove penicillin allergies during clinic visits.

Disclosures

All Authors: No reported disclosures
2212. Cessation of fluoroquinolone prophylaxis in inpatients with haematological malignancy – a retrospective cohort analysis
Authors: Bapat Anjaneya , Drumright Lydia N , Caldwell Louise , Jimenez-England Fergus , Lambourne Jonathan , Agrawal Samir
Published: November 2023

Background

Fluoroquinolone prophylaxis remains standard-of-care for inpatients with hematological malignancy expected to have prolonged neutropenia. However, there are increasing concerns about drug toxicities, the negative impact on the microbiome, antimicrobial resistance and mortality.

Methods

In our centre, ciprofloxacin prophylaxis was used for patients with acute leukaemia, high-risk myelodysplastic syndrome and those receiving a hematopoietic stem cell transplant until September 2019 (period T1). Thereafter, ciprofloxacin prophylaxis was stopped (period T2). This retrospective cohort analysis analysed 2391 admissions among 1089 patients between April 2017 and January 2022 for outcomes including mortality, Gram-negative bloodstream infection (GNBSI) and admission to the intensive care unit (ICU).

Results

Patients in T1 and T2 were well-balanced for age, gender, underlying diagnosis and treatments (Table 1). The cessation of fluoroquinolone prophylaxis was associated with a significant reduction in mortality (16.7% vs 11.0%, p=0.008), increase in GNBSI (8.5% to 12.4%, p=0.038), but no difference in ICU admissions (8.2 vs 8.3%, p=0.945). Patients in T2 who developed GNBSI had significantly lower rates of fluoroquinolone resistance (RR=0.32; 95% CI: 0.18 -0.56) and extended spectrum beta-lactamase production (RR 0.23; 95% CI: 0.09-0.55). In time updated Cox proportional hazard models, patients in T2 were significantly less likely to die than those in T1 (RR=0.46, 95% CI: 0.37-0.58) in fully adjusted models (Figure 1). The survival benefit seen in T2 patients was seen in both patients with, and without, GNBSI.

Table 1

Participant characteristics at first included visit for all ciprofloxacin prophylaxis eligible haemato-oncology inpatients by time period, fluoroquinolone prophylaxis (T1) given and no prophylaxis (T2) given

Figure 1

Survival over study time based on contributions to time period 1 with routine ciprofloxacin prophylaxis (T1) and time period 2 with no fluoroquinolone prophylaxis given (T2) among inpatients in haemato-oncology who were fluoroquinolone prophylaxis eligible (n=1089). Fully adjusted models are adjusted for age, sex, admitted through emergency, currently receiving hematopoietic stem cell transplant, cycle of treatment, and diagnosis.

Conclusion

The cessation of fluoroquinolone prophylaxis was associated with significantly lower mortality, lower antimicrobial resistance, no change in ICU admission rates but a higher recorded rate of GNBSI. It is possible that the widespread use of fluoroquinolone prophylaxis may have been causing harms in this patient population.

Disclosures

Anjaneya Bapat, FRCPath, Gilead: Honoraria Jonathan Lambourne, MB BS, BA, MSc, DTM&H FRCP, FRCPath, PhD, Mundipharma: Advisor/Consultant|Mundipharma: Advisor/Consultant Samir Agrawal, MD PhD, Pfizer: Grant/Research Support|Pfizer: Honoraria|Shionogi: Honoraria
2233. Burden of Bacterial Antimicrobial Resistance in United States in 2019: A Systematic Analysis
Authors: Amin Vishrant Prafulchandra , Dhanani Maulik , Patel Juhi , Dhawan Arushi , Mahesh Gangannapalle , Chenna Venkata Sai Harshabhargav , Kyada Sumit , Dekhne Anushka , Desai Hardik Dineshbhai
Published: November 2023

Background

The burden of AMR in the United States (US) is significant. According to the Centers for Disease Control and Prevention (CDC), at least 2.8 million people in the United States acquire antibiotic-resistant infections each year, and more than 35,000 people die as a result.

Methods

Using the Global Burden of Disease, Antimicrobial resistance (AMR) methodology, data were obtained on deaths and DALYs attributable to and associated with bacterial AMR for 23 pathogens in the US in 2019.

Results

In the US, there were 60,813 deaths (95% uncertainty interval [UI]:32,520-102,231) associated with and 14,987 deaths (95% UI:7,712-25,156) attributable to bacterial AMR in blood stream infection highest in 2019. Staphylococcus aureus (61,011) and E Coli (41,656) accounted for the majority of deaths attributable to and associated with AMR in 2019, and resistance was high among multiple types of antibiotic class. There is a significant burden of AMR in Staphylococcus aureus, with up to 50% of the resistance attributed to macrolides, 38% attributable to fluoroquinolones.

Deaths associated and attributable to bacterial antimicrobial resistance by pathogen in USA, in 2019

A) All age-counts B) Age-standardized Rate

Deaths Associated with and attributable to bacterial Antimicrobial resistance by syndrome in USA, in 2019

A) All age counts B) Age-Standardized Rate

DALYs attributable to and associated with bacterial antimicrobial resistance in USA, in 2019

A) Age-standardized DALY by Infectious Syndrome B) Age-Standardized DALY by Pathogen

Conclusion

AMR is a serious burden in the United States, with millions of people acquiring antibiotic-resistant infections each year and tens of thousands dying as a result. Preventing the spread of AMR requires a multifaceted approach that includes improved infection control practices, more judicious use of antimicrobial drugs, increased surveillance and monitoring of resistance patterns, and the development of new antibiotics and other treatment options.

Disclosures

All Authors: No reported disclosures
2243. Patterns of Micafungin Prescribing in the Intensive Care Unit in an Observational Retrospective Cohort
Authors: Cozzi Francesca E , Rodriguez Raul , Herald Fischer , Hodgson Hayley A , Sansom Sarah E , Shankaran Shivanjali , Varughese Christy A , Won Sarah Y
Published: November 2023

Background

Micafungin is restricted by the Antimicrobial Stewardship group at Rush University Medical Center (RUMC), but use in intensive care units (ICUs) is higher than predicted according to benchmarking data. Micafungin is frequently requested empirically for sepsis despite the lack of evidence to support a mortality benefit. The objective of this review was to characterize micafungin requests in the ICUs at RUMC.

Methods

Retrospective data was collected from June 2020 - August 2022 at RUMC, an academic tertiary care center in Chicago, IL with 104 adult ICU beds. Any patient with a new micafungin order during an ICU stay was reviewed for order appropriateness and clinical outcomes. Micafungin requests were classified as “empiric” or “documented candidiasis.” The primary outcome was incidence of fungemia on culture drawn 3 days before to 7 days after the micafungin order. Among empiric requests, incidence of invasive fungal infection (IFI), defined as fungi isolated in a culture from a sterile site, was also evaluated.

Results

232 new micafungin orders were placed during the study period, of which 51 (22%) were prescribed for documented candidiasis and 181 (78%) were empiric. Of patients for whom empiric micafungin was ordered, 18/181 (10%) subsequently developed an IFI. Of these, only 6/181 (3%) developed fungemia. Other IFI identified included 8/181 (4%) abdominal infections and 4/181 (2%) with positive miscellaneous cultures. 90% (163/181) of patients with an empiric micafungin order did not develop an IFI.

Conclusion

The overall incidence of critically ill patients who developed an IFI within 7 days of a micafungin request was very low. Data sharing, prescriber education, and additional stewardship interventions should be explored to improve the appropriateness of antifungal prescribing.

Disclosures

All Authors: No reported disclosures