bluuebunny/crossref_metadata_2025 huggingface dataset:
1835. Factors impact Longevity in Persons Living with HIV
Authors: Gill Arshpal , Oehler Cassandra , Kodavatiganti Srivastava , Baker Samantha , Hsiao Chiu-Bin
Published: November 2023

Background

In contrast to high mortality including young patient in 1990’s, persons living with HIV (PLWHIV) can expect a near-normal life expectancy of 77 years. Recent mortality data suggests significant number of HIV positive patients pass before the age of 70 years. There is a current paucity of literature looking at characteristics of the elderly PLWHIV when comparing to patients who died from HIV at a younger age. The goal of this study was to compare factors between the current HIV population living longer than age 70 and the population that did not survive until age 70 at the Positive Health Clinic (PHC). PHC is an urban city Ryan White funded HIV Care Medical Home Clinic, at Pittsburgh, PA, that provides care to ∼920 PLWHIV

Methods

A retrospective chart review of patient records at PHC; with patients from period between 2015 -2022 was queried for HIV viral load, recent CD4 counts, and social history. Smoking, alcohol, and drug use were used as primary social measures due to their known impact in early development of prevalent chronic comorbidities. A Chi squared test was then employed to analyze for statistical significance of these factors (P < 0.05) between the cohort of patients that are living beyond the age of 70 (longevity) and the cohort of patients who died prior to age of 70

Results

A total of 149 records were obtained (122M/ 27F, 95W/54B). The median age of HIV diagnosis and death was 44 and 60, respectively. There was no statistical difference between two groups in gender, race, and initial HIV transmission route, but being diagnosed with HIV after the age of 40 was associated with longevity. Unsurprisingly, patient with last viral load above 500 or CD4 below 200 were less likely to survive past age 70. HIV viral load < 200, persistently, in past 5 years and absence of smoking in last 15 years were the 2 factors most strongly associated longevity. Alcohol abuse and drug use were less likely to survive age 70. Statistical data between the two groups are listed in Table attached.

Comparing factors associated with living beyond 70 versus dying before 70

Conclusion

Common comorbidities such as diseases of heart, lung, kidney and cancer are impacted by substance misuse, and as a result may serve as a barrier to reaching old age in PLWHIV. Counseling against tobacco use, treatment of alcohol and drug addiction while sustaining viral control with HAART can promote the longevity of PLWHIV.

Disclosures

Chiu-bin hsiao, MD, Gilead: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support|ViiV: Honoraria
1851. ID Fellow Quality Improvement Project Shows Gains in Oral Health Exams for People with HIV
Authors: Park Terrence , Richey Lauren , Seal Paula
Published: November 2023

Background

Oral Health is important in people with HIV and remains an important HRSA performance measure. This HRSA measure is the percentage of people with HIV who had an oral health exam by a dentist in the performance year out of the people who had a medical visit in that same year. Our clinic is unique in that it has a Ryan White funded dental clinic with 3 full-time dentists on site. The percentage of patients receiving an oral health exam had decreased in recent years due to shutdowns and fear during the COVID-19 pandemic as well as the vaccine and testing requirements implemented for safety.

Methods

A quality improvement project was designed by an infectious diseases fellow to improve the number of patients receiving an oral health exam. The project was multipronged. The first step was educating the HIV providers about how to place a referral to the HIV dental clinic. The second was placing educational posters in each exam room to educate the patients about the importance of oral health and encourage them to ask for a referral. The last was giving each patient a questionnaire when they checked in for their visit. Each patient filled in the date of their last oral health exam, where it was received, and willingness to be referred for an oral health exam if not examined in the past 12 months. The questionnaires were collected by the provider and served as a reminder to refer. Our goal was a 40% improvement over our baseline, which was 23% in 2020 (goal >32.2%). The intervention began in September of 2022.

Results

In 2019, 31% of our HIV primary care patients were seen in the attached dental clinic, this dropped to 23% in 2020 and 24% in 2021. In the three months prior to our intervention, 38% of patients were referred, and 286 patients had an oral health exam; during the intervention 56%(n=388) of patients were referred, and 329 had an oral health exam. In 2022, 33% of HIV primary care patients were seen in the attached dental clinic, showing an increase despite only three months of the intervention.

Conclusion

Early results indicate an increase in the referrals and an oral health exams with this quality improvement intervention. Outcomes were limited by significant no shows and confounded by removal of COVID vaccine and testing requirements.

Disclosures

All Authors: No reported disclosures
1856. Barriers to Improving Outcomes among People Experiencing Homelessness and People Who Inject Drugs Hospitalized for Complicated Infections
Authors: Parke Dana M , Kenney Rachel M , Bogojevich John , El-Khoury Caren , Joshi Seema , Brar Simran , MacDonald Lynsey , Salib Christina , MacDonald Nancy , Veve Michael , Suleyman Geehan
Published: November 2023

Background

People experiencing homelessness (PEH) and people who inject drugs (PWID) experience health disparities and worse outcomes. Challenges include suboptimal medication use, loss to follow-up, and non-compliance due to social determinant of health (SDOH) barriers, including lack of stable housing and transportation, limited financial resources, substance use, and addiction.

Methods

This quality improvement project aimed to address SDOH barriers among hospitalized PEH and/or PWID requiring ≥ 2 weeks of antibiotics to improve antibiotic compliance and outcomes in Detroit from 6/2022-4/2023. Interventions included antibiotic education, addiction medicine and pharmacy discharge medication cost inquiry consults when indicated, ensuring oral antibiotics were in hand at discharge, strengthening discharge planning between inpatient and ambulatory case managers (ACM), and referrals to community-based organizations to address SDOH needs.

Results

34 patients were included (8 PEH, 11 PWID, 15 both); 3 who died in the hospital were excluded. Multiple individual and structural barriers and challenges to improving adherence and outcomes were identified (Table 1). Loss to follow-up was a significant challenge among this cohort, primarily due to patients self-discharging (29%) and being unreachable (52%). 10 (37%) patients were offered SDOH services (Table 2). Patients also had significant behavioral health/substance use disorder needs and utilized healthcare at a very high rate, with 29% having an ED revisit and 44% being readmitted within 30 days after discharge. Several structural and SDOH barriers existed, including limited staff capacity and limited placement options after discharge, resulting in suboptimal treatment delivery.

Conclusion

Addressing SDOH barriers for PEH and PWID is challenging but vital to improving outcomes. Qualitative research should be conducted to understand these barriers. Having an interdisciplinary team comprising of infectious diseases, pharmacy, addiction medicine, case management and population health is critical to address patient needs holistically. Strengthening internal processes and building additional community-based partnerships will be essential to better meet patient needs after discharge.

Disclosures

Michael Veve, PharmD, MPH, National Institutes of Health: Grant/Research Support|Paratek Pharmaceuticals: Grant/Research Support
1865. Refractory Nontuberculous Mycobacterial Pulmonary Disease: Natural History and Burden of Illness in Patients from the US Bronchiectasis and NTM Research Registry (BRR)
Authors: Aksamit Timothy R , Choate Radmila , Mannino David M , Brunton Amanda E , Wang Ping , Hassan Mariam
Published: November 2023

Background

Nontuberculous mycobacterial pulmonary disease (NTMPD) is a chronic lung infection that is challenging to treat, especially refractory NTMPD. Data are limited on the natural history, risk profile, and burden of refractory NTMPD. The objective of this study was to evaluate the burden of illness (BOI) among patients with NTMPD who later develop refractory NTMPD vs those who do not.

Methods

This was a retrospective analysis using BRR data. Patients treated for NTMPD were included and stratified as refractory (received oral clofazimine/bedaquiline or inhaled amikacin/ALIS, or remained sputum culture positive despite ≥ 6 months of treatment) or nonrefractory. Modified bronchiectasis severity index (mBSI) at baseline visit and BOI including comorbid conditions and surgeries at the treatment visit were compared by cross-sectional analysis between the two groups. Longitudinal analysis of BOI focused on exacerbations and hospitalizations in the refractory group at their pre-refractory visit and refractory visit (first visit meeting the refractory definition).

Results

A total of 1,064 patients treated for NTMPD were included: 462 (43.4%) refractory and 602 (56.6%) nonrefractory. During the baseline period, the refractory group had more severe bronchiectasis (Table 1, mBSI, mean [SD], 7.3 [3.4] vs 6.7 [3.4]). At the time of treatment, bronchiectasis was more common in the refractory than nonrefractory (96.2% vs 89.7%) group, as were hemoptysis (26.6% vs 16.3%) and GERD (50.5% vs 39.9%). Except BMI, there were no statistically significant differences between the pre-refractory and nonrefractory treatment visits (Table 2). In the refractory group, exacerbations and hospitalizations remained high from the pre-refractory to refractory visit (45.6% vs 39.4% and 13.3% vs 12.8%, respectively). Oxygen and bronchial hygiene use increased from the pre-refractory to the refractory visit (5.2% vs 9.3% and 54.5% vs 61.7%, respectively) consistent with increased management of respiratory conditions when not responding to treatment (Table 2).

Conclusion

Refractory NTMPD imposes a high disease burden on patients in the BRR. This high burden was present at pre-refractory visits and through the development of refractory status.

Disclosures

Timothy R. Aksamit, MD, AstraZeneca: Advisor/Consultant|Baxter International, Hill-Rom: Advisor/Consultant|Insmed Incorporated: Advisor/Consultant|Johnson & Johnson: Advisor/Consultant|Redhill Biopharma: Advisor/Consultant|RespirTech: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Zambon: Advisor/Consultant David M. Mannino, MD, AstraZeneca: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Up to Date: Advisor/Consultant Ping Wang, PhD, Insmed Incorporated: Salary|Insmed Incorporated: Stocks/Bonds Mariam Hassan, PhD, B. Pharm, Insmed Incorporated: Salary|Insmed Incorporated: Stocks/Bonds
1871. Lessons Learned from IGRA Test Practices in a Tertiary Hospital
Authors: Daas Farah , Ruiz-Gaviria Rafael , Thummar Bhakti , Khan Naveera , Ramdeen Sheena
Published: November 2023

Background

Interferon Gamma Release Assay (IGRA) is frequently ordered in hospitalized patients for latent tuberculosis (TB) screening. Health care workers must be cautioned that acute and critical illness exert a significant effect on IGRA performance, so delaying screening to the outpatient setting is preferred if feasible. When active TB is suspected, IGRA can aid in risk stratification, particularly in areas with low prevalence of TB, but should not be used to confirm or rule out active TB infection. False negative IGRA results in active TB are estimated to be up to 20%. Current guidelines from the Centers for Disease Control and Prevention, the Infectious Diseases Society of America and the American Thoracic Society suggest that IGRA cannot distinguish active from latent TB and recommend prompt microbiological testing when active TB is suspected.

Methods

We conducted a retrospective chart review on hospitalized patients older than 18 years in a tertiary academic center who had an IGRA test done from January 1, 2021, to December 31, 2021. We randomly selected 78 from the 417 identified patients for collection of encounter level data.

Results

IGRA test indications were screening for latent TB in 53.8%, to investigate active pulmonary TB in 30.8%, and for other reasons in 6.4%. IGRA tests had no clear indication in 9% of cases. IGRA test results were 84.6% negative; 10.3% positive; and 5.1% indeterminate. After a negative IGRA, microbiological testing was ordered in 12%, with 1 positive test confirming active TB.

Active TB was suspected in 30.8% of our cohort. Microbiologic testing was done in 41.6% of these patients. In most of the patients with microbiological testing, ordering was delayed until a positive IGRA was available with an average delay of 2.4 days.

Conclusion

Collection of sputum for microbiological testing should not be delayed until IGRA test results are available, and negative results should be scrutinized when suspicion for active TB is high. Caution must be practiced in interpreting IGRA results, and we should not solely rely on IGRA in decision-making regarding isolation, treatment, or further testing. Education of health care staff may be required regarding the indications and timing of IGRA testing.

Disclosures

All Authors: No reported disclosures
1878. Short message service (SMS) alert and reschedule an appointment to shorten physician delay of TB treatment: A quasi-experimental study
Authors: Angkasekwinai Nasikarn , Guayboon Theerajet , Ngamskulrungroj Popchai
Published: November 2023

Background

Tuberculosis (TB) continues to pose a major health threat during the ongoing coronavirus diseases 2019 (COVID-19) pandemic in Thailand. Delays of TB treatment either due to patients or healthcare system resulted in an unfavorable outcome. There is limited study using information technology to diminish physician delay of TB treatment.

Methods

This was a quasi-experimental study conducted from June 2019 to February 2022 at Siriraj Hospital to assess the impact of using the short message service (SMS) alerts and rescheduling an appointment to shorten the physician delay in starting TB treatment. Patients were eligible if they were ≥18 years and having a positive TB test results by either one of the following: acid-fast bacilli (AFB) smear, polymerase chain reaction (PCR) for TB, or mycobacterial culture reporting M. tuberculosis complex. The primary outcome was the duration from reporting the first positive TB test to the treatment initiation.

Service flow and interventions, including SMS notification and rescheduling service.

Figure 2

Screening, exclusion and analysis populations in pre-implementation or routine care and post-implementation of SMS service.

Results

Among 364 patients, 206 patients and 158 patients were included in the no SMS and the SMS groups, respectively. The SMS group had a significantly higher proportion of being treated in the OPD setting (94.3% vs 67%, p< 0.001), treated by staff (42% vs. 23.5%, p< 0.001), and treated by pulmonologists (54.4% vs. 36.2%, p=0.004) than the no SMS group. Patients in the SMS group had a longer median time from the first visit to treatment (29 days [14.0, 57.8] vs.12 days [5.0, 47.5], p< 0.001), specimen collection to treatment (15.5 days [7.0, 31.8] vs. 6.5 days [2.0, 22.8], p< 0.001), and reporting results to treatment (9 days [5.0, 16.0] vs. 3.5 days [1.0, 12.0], p< 0.001) than the no SMS group. However, among TB patients being treated in the OPD setting and having a culture as the first positive result, those in the SMS group had a significantly shorter median time from specimen collection to treatment than the no SMS group (36 days [29.0, 51.0] vs. 60 days [39.0, 101.0], p=0.018). The median time from reporting the results to treatment was also shorter in the SMS group (9 days [6.0, 30.0] vs. 25 days [6.3, 81.0], p=0.172) but there was no statistically significant difference.

Conclusion

SMS notification could reduce healthcare system delays in the initiation of TB treatment among TB patients who have positive mycobacterial cultures, but negative AFB smear and PCR-TB.

Disclosures

All Authors: No reported disclosures
1879. Paradoxical Reaction in Lymph Node Tuberculosis among HIV-negative Patients: Incidence, Predictive Factors, and Clinical Outcomes
Authors: Gupta Ankesh , Kumar Santosh , Jorwal Pankaj , Singh Binit K
Published: November 2023

Background

The aim of this study is to evaluate the occurrence of paradoxical reactions (PRs), cytokine levels and outcome in HIV-negative lymphnode tuberculosis (TB) patients.

Methods

This is a prospective observational study conducted at the All-India Institute of Medical Sciences in New Delhi, India from July 2019 to June 2021. 144 subjects with confirmed or probable lymph node TB, excluding MDR TB, were recruited. Baseline characteristics, clinical presentation, imaging, laboratory parameters, and TB diagnostic modalities were gathered. Patients were followed up to evaluate the occurrence of PRs, and cytokines IL2, IL6, IL18, and TNF alpha were analyzed using the sandwich ELISA principle at baseline and after PR development.

Workflow of the study.

Results

Total 144 subjects with confirmed tuberculosis were recruited. PRs developed in 5.5% of patients, with fever (58.74%) and weight loss (44.06%) being the predominant systemic symptoms. The median time for PR development was 37 days, with pain and swelling being the most common presentation (62.5%). Among the baseline cytokines, IL6 was the most elevated (20.83%), with IL2, IL18, and TNF alpha being elevated in 8.3%, 0.69%, and 1.38% of the subjects, respectively. On multivariate analysis, baseline elevation of interleukin 2 was statistically significant and predicted PRs. IL2 and IL6 were significantly elevated during the occurrence of PRs, while IL18 and TNF alpha were not. Most patients (75%) improved on NSAIDs, with a median symptom resolution duration of 30 days.

Comparison of patient parameters at baseline and after the development of paradoxical reactions.

Comparison of cytokine levels at baseline and after paradoxical reactions.

Paradoxical reaction features, tuberculosis diagnostic modalities and treatment modalities of paradoxical reaction.

Conclusion

Our study found that baseline elevation of IL-2 and worsening adenopathy and weight loss during treatment are potential predictors for paradoxical reaction in lymph-node tuberculosis. However, it is important to validate these findings through larger prospective studies.

Disclosures

All Authors: No reported disclosures
1896. Analysis of Virulence Factors and Antibiotic Resistance Genes in Mycobacterium abscessus Prophage Sequences genomes and Relationships with Clinical Patient Prognoses
Authors: Sichun Luan
Published: November 2023

Background

M. abscessus is known for its multiple resistance to antibiotics, and diseases caused by M. abscessus have limited methods to treat with. Little is known for prophages carried by M. abscessus, nor their role played in diseases.

Methods

Strains identified as M. abscessus from patients from December 2017 to August 2021 were included. Prophages, virulence factors and antibiotic resistance genes in genomes were analyzed. The correlation between prophages, virulence factors and antibiotic resistance genes contained, and clinical patient prognoses were analyzed. The sequence similarity between prophages and known phages were analyzed.

Results

A total of 145 prophage sequences were detected in 56 M. abscessus strains. The average number of intact prophages was 0.7 ± 0.6. The average number and gene proportion of virulence factors and drug resistance genes in prophages were higher than those in known mycobacteriophages. Differences of average prophage carried, virulence factors and drug-resistant genes, and their proportions between different prognoses were not statistically significant, except for virulence factors. The average similarity of prophage sequences in single patient was 99.86%; which was significantly higher of the average matching rate of 89.27% in different patients and the total similarity of 78.28% between prophages and known phages. No clear positive correlation between tested common virulence factors or virulence factors and clinical patient prognoses was observed.

Conclusion

M. abscessus commonly carries prophages, and they have higher contents of virulence factors and drug resistance genes than known phages. The prophage detected in patients with good prognosis carried more virulence factors, and its meaning was unclear. The composition of the prophage sequences in the strains isolated from the same patient is stable, with occasional base mutation or deletion. Prophages carried in strains of different patients were highly diverse, and shared low similarity with known mycobacterium phages.

Disclosures

All Authors: No reported disclosures
1900. Disseminated and Extrapulmonary Nontuberculous Mycobacteria (NTM): Disease Management, Adverse Treatment Reactions, and Outcomes
Authors: Wang Heather , Sobhanie Mohammad Mahdee , Nichols Courtney
Published: November 2023

Background

Guidelines for the management of pulmonary nontuberculous mycobacterial (NTM) infections are well defined; however, similar guidelines for the treatment of disseminated or extrapulmonary NTM infections are lacking. This study aimed to describe our institutional experience in the treatment of disseminated and extrapulmonary NTM infections, and to better characterize the disease course, management, and outcomes in this patient population.

Methods

This single-center retrospective study was conducted at The Ohio State University Wexner Medical Center in patients who were diagnosed with disseminated or extrapulmonary NTM infection from November 1, 2011 to November 1, 2021. Only index cases were included in patients with a documented culture positive for an NTM, and patients with a positive pulmonary culture were only included if they had a documented extra-pulmonary site as well.

Results

58 patients met inclusion criteria and 54 were started on antibiotic therapy. 41.4% (N=24) and 31.0% (N=18) were started on two and three antibiotics as initial therapy, respectively. 32 (59.3%) patients required changes to their initial regimen, of which 31.3% (N=10) were changed due to intolerance or adverse event. The mean time to onset of antibiotic intolerance or adverse drug events was 129.4 days (6-404 days). 67.2% (N=39) of patients had documented resolution of their infections, with 7 patients currently on antibiotic therapy at the end of the study period (38.9%).

The most common antibiotic classes used included macrolides (64.8%), carbapenems (35.2%), ethambutol (25.9%), and aminoglycosides (22.2%). The antibiotic classes with most frequent intolerances were linezolid (42%), aminoglycosides (31.6%) and clarithromycin (21.0%) at a mean duration of 39.3, 72.2, and 32 days, respectively.

Table 1. NTM infection characteristics, including infection site, species breakdown, and disease outcome.

Table 2. NTM treatment regimen details and reasons for changing and/or not completing planned antibiotic regimen for all study patients.

Table 3. Breakdown of antibiotic classes used in initial treatment regimens for dNTM-infected patients, along with antibiotics that caused patient intolerances. For each antibiotic class that caused intolerance, average time to develop intolerance listed.

Conclusion

Treatment of disseminated and extrapulmonary NTM infections typically requires a complicated treatment course due to prolonged durations of multiple antibiotics, patient intolerances to antibiotic classes, and difficulty with determining appropriate end of therapy timing. Additional studies are needed to better outline the ideal antibiotic regimens and duration for disseminated and extrapulmonary NTM infections.

Disclosures

All Authors: No reported disclosures
2129. Antimicrobial Activity of Cefepime in Combination with Taniborbactam Against Resistant Clinical Isolates from the United States 2018-2021
Authors: Hackel Meredith , Wise Mark G , Sahm Daniel F
Published: November 2023

Background

Taniborbactam is a novel, investigational broad-spectrum β-lactamase inhibitor with direct inhibitory activity against both serine- and metallo-β-lactamases. Taniborbactam restores the activity of cefepime (FEP) against many difficult to treat organisms, including cephalosporin- and carbapenem-resistant Enterobacterales (EB) and Pseudomonas aeruginosa (PA). The activity of cefepime-taniborbactam (FTB) and comparator agents was evaluated against nonsusceptible (NS)/resistant (R) clinical isolates of EB and PA from the United States (US) collected in global surveillance.

Methods

MICs of FTB (taniborbactam fixed at 4 µg/mL) and comparators were determined using the CLSI reference method against EB (n=4,220) and PA (n=1,222) from the US collected in 2018-2021. NS/R phenotypes were based on 2023 CLSI breakpoints (EUCAST breakpoint for meropenem-vaborbactam [MEV] against PA). Multidrug R (MDR) was defined as R to ≥1 agent from ≥3 drug classes.

Results

Overall, 13.1% and 10.3% of EB isolates were NS to FEP and piperacillin-tazobactam (TZP), respectively (Table). FTB had potent activity against all EB (MIC50/90, 0.03/0.12 µg/mL; 99.9% inhibited at ≤16 µg/mL). FTB maintained activity against NS/R subsets of EB (MIC90 range, 1 to 8 µg/mL; 90.0% to 99.3% inhibited at ≤16 µg/mL) including MDR isolates (MIC90, 2 µg/mL; 98.4% inhibited at ≤16 µg/mL). FTB was the most active tested agent against PA overall (MIC50/90, 2/8 µg/mL; 97.7% inhibited at ≤16 µg/mL). Among meropenem (MEM)-NS isolates, 91.2% were inhibited by FTB at ≤16 µg/mL compared to 76.6% susceptible to ceftolozane-tazobactam (CT). FTB at ≤16 µg/mL inhibited 74.2% of CT NS isolates of PA whereas 47.2% of isolates of this phenotype were susceptible to ceftazidime-avibactam (CZA). Against MDR PA (13.4% of all PA), FTB (MIC50/90, 8/32 µg/mL) inhibited 85.4% of isolates at ≤16 µg/mL compared to 59.1% that were susceptible to CT.

Conclusion

Cefepime-taniborbactam had potent in vitro activity against recent EB and PA from the US, including MDR isolates and isolates NS to FEP, MEM, TZP, CZA, CT, and/or MEV. These data support continued development of cefepime-taniborbactam as a potential treatment option for challenging infections due to resistant Gram-negative pathogens.

Disclosures

Meredith Hackel, PhD, Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Mark G Wise, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation Daniel F. Sahm, PhD, Merck & Co., Inc.: Honoraria|Pfizer Inc.: Honoraria|Venatorx: Paid fees for conducting the study and abstract preparation
2130. Safety and Pharmacokinetics of SPR206 in Subjects with Varying Degrees of Renal Impairment
Authors: Bruss Jon , Bader Justin C , Hamed Kamal
Published: November 2023

Background

SPR206 is a novel polymyxin derivative with potent in vitro activity against susceptible and multidrug-resistant strains of Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, Escherichia coli, and Enterobacter species. In nonclinical studies, SPR206 had similar or greater activity than polymyxin B with an improved safety profile.

Methods

We evaluated the safety, tolerability, and pharmacokinetics (PK) of SPR206 in healthy subjects with normal renal function and subjects with various degrees of renal impairment (RI) or end-stage renal disease (ESRD) on hemodialysis (HD). All subjects except those with ESRD on HD received a single 100 mg dose of SPR206 as a 1-hour intravenous (IV) infusion. Subjects with ESRD on HD received a 100 mg IV dose within 2 hours after HD on Day 1 (Period 1) and 1 hour before HD on Day 5 (Period 2).

Results

Among 37 subjects, no deaths, treatment-related serious adverse events (AEs), or discontinuations due to AEs were reported. Paresthesias were the most common treatment-related AEs. Systemic exposure to SPR206 increased as RI worsened, with mean AUC

0-last of 39% to 239% greater with mild to severe RI vs. healthy subjects (Figure). Renal clearance (CL) decreased (1.2 L/h to 0.13 L/h) with decreasing renal function, and plasma CL was 29% to 76% lower with RI vs. healthy subjects. In subjects with ESRD on HD, mean AUC0-last was 372% greater and mean CL was 87% lower in Period 1 (nondialyzed) vs. healthy subjects. In Period 2 (dialyzed), AUC0-last was 131% greater and CL was 75% lower vs. healthy subjects. In subjects with ESRD on HD, SPR206 systemic exposure (AUC0-last) decreased by 51% and CL increased by 92% during dialyzed vs. nondialyzed conditions. AUC was negatively correlated and CL positively correlated with estimated glomerular filtration rate (eGFR) (p< 0.0001). SPR206 was mostly excreted in urine within 12 hours in healthy subjects and subjects with mild RI, but excretion was slower in subjects with moderate and severe RI. HD was effective in removing SPR206 from the circulation.

Conclusion

In summary, SPR206 appeared to be safe and well tolerated in subjects with varying degrees of RI including those with ESRD on HD. These results will inform dose adjustments in future studies for patients with various degrees of RI including those with ESRD on HD.

Disclosures

Jon Bruss, M.D., Spero Therapeutics, Inc.: employee Justin C. Bader, PharmD, Spero Therapeutics, Inc.: former employee Kamal Hamed, MD, MPH, Spero Therapeutics, Inc.: current employee
2142. The use of Pseudomonas aeruginosa Phage PASA16 for non resolving infections
Authors: Onallah Hadil , Hazan Ronen , Nir-Paz Ran
Published: November 2023

Background

A growing number of compassionate phage therapy use cases reported in the last decade, with only a limited number of clinical trials conducted and very few unsuccessful clinical trials reported. However, the limited understanding of individual clinical cases and lack of successful published clinical trials provides little evidence on the role of phages in refractory infections. Our objective was to bridge between single cases to early clinical trials and to describe the compassionate use of a single same phage - PASA16 - in sixteen patients with non-resolving Pseudomonas aeruginosa infections.

Methods

We have collected all cases in which PASA16 was used and summarized clinical microbiology data, administration protocol, clinical data and outcome. In all instances involving intravenous phage administration (14 out of 16 cases), PASA16 phage was manufactured and provided pro-bono by Adaptive Phage Therapeutics.

Results

PASA16 was administered either IV, locally to infection site or by topical use to 16 patients, with data available for 15 patients, mainly for osteoarticular and foreign device associated infections. Few minor side effects were noted including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 (86%). Two clinical failures were reported.

Conclusion

PASA16 with antibiotics was found to be relatively successful in patients who have failed previously in traditional approaches. Minimal successful duration of phage therapy was 8 days with once to twice a day administration. Such pre-phase 1 cohorts can outline the potential clinical protocols to be used and facilitate the design of future clinical trials.

Disclosures

Ran Nir-Paz, MD, Adaptive phage theraputics: Supplied the phage product for this study|BiomX: Advisor/Consultant|Technophage: Grant/Research Support
2144. A Phase 1, Multicenter, Open-Label, Parallel-Group Study to Assess the Safety and Pharmacokinetics (PK) of Oral Epetraborole Tablets in Adult Subjects with Varying Degrees of Renal Function
Authors: Patel Gina , Canas George C , Cruz Kimberly , Marbury Thomas C , Gotfried Mark , Chan Wallace (Boon Chun) , Duchin Kenneth , Maier Gary , Chanda Sanjay , Kammerer Linda , Long Jennifer , Moore Stephanie , O’Shea Kevin , Shafiee Afshin , Smith Alex , Eckburg Paul B
Published: November 2023

Background

Epetraborole (EBO), an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria, is in clinical development for treatment-refractory MAC lung disease. The objective of the study was to evaluate EBO PK in adult subjects with varying degrees of renal impairment (RI) including end stage renal disease (ESRD) with intermittent hemodialysis (IHD).

Methods

Open-label, single-dose EBO 500 mg PO was given to subjects in 5 cohorts: normal renal function, mild, moderate, and severe RI, and ESRD-IHD (Table); ESRD subjects received a second 500 mg dose on Day 5 approximately 1 hour before receiving IHD. EBO and its inactive major metabolite (M3) concentrations in plasma, urine and dialysate were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods and compared among cohorts using analysis of variance (ANOVA). Standard clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed.

Results

40 subjects were enrolled (8/cohort). Subjects with RI did not exhibit quantitatively distinct EBO plasma PK profiles compared to those with normal renal function; AUC mean ratios were 110-140% in subjects with RI, and the mean ratios of maximum observed concentration (Cmax ) values did not exceed 116% (Table). The elimination half-life (t1/2) increased slightly from 9.3 to 11.0 h in ESRD subjects, and clearance decreased by about 30%. Renal elimination was not a major route of excretion (∼15% of dose over 72 h) for EBO, with mean renal clearance ranging from 4.24 L/h to 1.04 L/h. Metabolite M3 AUC increased 4-fold in subjects with severe RI, and t1/2 increased from 20 to 32 h. EBO was well tolerated; 7 subjects (17.5%) experienced at least 1 TEAE (11 events), all mild in severity except 1 moderately-severe TEAE of worsening anemia. There were no severe or serious TEAEs.

Conclusion

Minimal increases in plasma EBO exposures and similar t1/2 values were observed in subjects with varying degrees of RI, including ESRD-IHD. Single 500 mg doses of EBO were well tolerated in each RI cohort. Overall, these data suggest that no dose adjustment of EBO is needed in subjects with any degree of RI.

Disclosures

All Authors: No reported disclosures
2148. In vitro Potency of a Leucyl-tRNA Synthetase Inhibitor, MRX-6038, Against Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium abscessus
Authors: Shoen Carolyn M , DeStefano Michelle S , Wang Wen , Cynamon Michael H
Published: November 2023

Background

The family of Mycobacteriaceae contains hundreds of species, some causing diseases in humans. The most well-known is Mycobacterium tuberculosis (Mtb), the causative agent for tuberculosis. Approximately 2 billion people are infected with M. tuberculosis. Drug-resistant strains of M. tuberculosis have emerged in the last 30 years, making the development of newer, effective drugs important. Non-tuberculous mycobacteria (NTM) cause difficult to treat infections. M. abscessus (Mabs) and M. avium (MAC) fall within this category. Drug-resistance and/or drug tolerance is a serious hurdle in trying to control NTM infections. The goal of this study was to evaluate the in vitro activity of a novel leucyl-tRNA synthetase inhibitor, MRX-6038, against Mtb, MAC, and Mabs.

Methods

MRX-6038, epetroborole (EBO), and GSK656 (GSK) was provided by MicuRx Pharmaceutical Co., Ltd. Clarithromycin (CLR) and isoniazid (INH) were purchased from Biosyth Ltd and Sigma-Aldrich Chemical Company, respectively. Stock solutions were dissolved in 100% DMSO and frozen at -20oC until used. Drugs were serially diluted in cation adjusted Mueller-Hinton broth (CAMHB) (Mabs), CAMHB with 5% OADC (MAC), and 7H9 Broth with 10% OADC (Mtb) in microtiter plates for MIC evaluation in duplicate. Wells were inoculated with ∼ 1.25 x 105 CFU/ml of bacteria. Plates were incubated for 4-5 (Mabs), 7 (MAC), or 14 (Mtb) days at 37oC in ambient air. The MIC is defined as the lowest concentration of drug that yielded no visible turbidity.

Results

The MIC50 and MIC90 (µg/ml) of the MAC isolates against CLR, EBO, and MRX-6038 were 1 and 4, 1 and 8, and 1 and 8, respectively. The MIC50 and MIC90 of the Mabs isolates against CLR, EBO, and MRX-6038 were 8 and 16, 0.125 and 0.25, and 0.25 and 0.25, respectively. The MIC50 and MIC90 of the Mtb isolates against INH, GSK, and MRX-6038 were 1 and 8, 0.06 and 0.06, and 0.5 and 1, respectively. Many of the Mtb isolates used were known to be MDR strains.

Conclusion

The in vitro activity of MRX-6038 was quite promising against Mabs, MAC, and Mtb. Based on work by others, MRX-6038 has shown encouraging in vivo activity against Mabs in mice. The next steps will be to determine the in vivo activity against both MAC and Mtb infection in mice.

Disclosures

Wen Wang, PhD, MicuRx Pharmaceuticals: Employee of
2153. Addition of Relebactam Increases Susceptibility to Imipenem Alone against Class C β-lactamase-Positive Enterobacterales: Asia/Pacific SMART 2019-2021
Authors: Lob Sibylle , Wise Mark G , Chen Wei-Ting , Siddiqui Fakhar , Young Katherine , Motyl Mary , Sahm Daniel F
Published: November 2023

Background

Imipenem/relebactam (IMI/REL) is a combination of imipenem/cilastatin with the β-lactamase inhibitor relebactam, an inhibitor of class A and C β-lactamases. We evaluated the activity of IMI/REL and comparators against AmpC- and extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae as well as against isolates of intrinsic AmpC-producing Enterobacterales species that were collected in 9 countries in Asia/Pacific as part of the global SMART surveillance program.

Methods

In 2019-2021, 48 clinical laboratories in Australia, Hong Kong, Malaysia, New Zealand, Philippines, South Korea, Taiwan, Thailand, and Vietnam each collected up to 250 consecutive, aerobic or facultative, gram-negative pathogens per year from patients with bloodstream, intraabdominal, lower respiratory tract, and urinary tract infections. MICs were determined using CLSI broth microdilution and interpreted with 2023 CLSI breakpoints. Isolates that were imipenem-, IMI/REL-, or ceftolozane/tazobactam-nonsusceptible (NS) were screened for β-lactamases.

Results

IMI/REL maintained activity against ≥96% of K. pneumoniae and E. coli that carried ampC with or without ESBL, and the addition of relebactam increased the susceptibility to imipenem alone by 13-54 percentage points among these isolates (Table). IMI/REL maintained activity against ≥92% of intrinsic ampC carriers, and the largest increase by addition of relebactam to imipenem alone was seen among K. aerogenes (25 percentage points). For imipenem-NS isolates, relebactam restored susceptibility to 98.3% of imipenem-NS ampC-positive K. pneumoniae (n=58), and to 96.8%, 97.3%, and 29.5% of imipenem-NS Enterobacter spp. (n=125), K. aerogenes (n=147), and S. marcescens (n=61) that carried no acquired β-lactamases, respectively.

Conclusion

IMI/REL showed strong activity against clinical Enterobacterales isolates that carried either acquired or intrinsic ampC with or without ESBL collected in Asia/Pacific. The addition of relebactam increased susceptibility to imipenem alone by up to 54 percentage points.

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
2158. An outbreak of carbapenem-resistant Acinetobacter baumannii at a tertiary hospital in Ethiopia
Authors: Adbaru Mulatu G , Gudina Esayas K , Kroidl Arne , Wieser Andreas
Published: November 2023

Background

Since there are no effective alternative treatments, health professionals in resource-constrained countries struggle to treat infections caused by microorganisms those are resistant to carbapenem antibiotics. The purpose of this study was to determine the magnitude of carbapenem-resistant Acinetobacter baumannii isolated from patients with surgical site infection.

Methods

A cross-sectional study was conducted among patients who underwent surgical procedures at Jimma Medical Center. Two wound swab samples were collected from patients who had clinical evidence of surgical site infection (SSI) and processed at JMC microbiology laboratory. All A. baumannii species were confirmed by MALDI TOF MS and the carbapenem-resistant isolates were further characterized using PCR.

Results

Of 1205 participants enrolled in the study, more than one-fourth (312) of them showed clinical evidence of SSI. A couple of wound swabs were collected from 83.3% (260) of the patients who had SSI for microbiological analysis. Of those, 72%, (189/260) were culture positive with 252 isolates and 36 different bacterial species. Acinetobacter baumannii, (20.2%; 51) were the second most frequent bacteria and showed the highest resistance to carbapenem antibiotics. The PCR analysis revealed blaOXA-51 60.8% (31/51) was the predominant carbapenemase-encoding gene followed by blaNDM 23.5% (12/51), and blaVIM, blaOXA-23, and blaOXA-58 (15.7%; 8 each) genes. About 37.3% (19) of the strains were co-harboring two or more resistance-encoding genes for carbapenem antibiotics.

Conclusion

It is concluded that A. baumannii is one of the predominant bacteria causing SSIs. The resistance genes blaOXA-51 and blaNDM-1 were highly prevalent in the strains. In light of this finding, it is recommended that current antimicrobial resistance surveillance programs and infection prevention practice and control measures should be re-evaluated.

Disclosures

All Authors: No reported disclosures
2164. Resistome patterns associated with vancomycin non-susceptibility in clinical Clostridioides difficile isolates
Authors: Eubank Taryn A , Gonzales-Luna Anne J , Hanson Blake M , Treangen Todd , Earl Ashlee , Garey Kevin W
Published: November 2023

Background

Clostridioides difficile exhibits phenotypic resistance to multiple classes of antibiotics. Associated antibiotic resistance genes (ARGs) are commonly transferred via mobile genetic elements, which often carry distinct ARG groupings. Increases in vancomycin non-susceptible C. difficile have been reported and understanding associated trends in ARG co-carriage are critical for strain transmission dynamics. Here we aimed to determine C. difficile resistome patterns associated with vancomycin non-susceptibility (NS).

Methods

Whole genome sequencing (WGS) was performed (Illumina NextSeq 500) on C. difficile isolated from adult patients hospitalized with C. difficile infection in two health systems (14 hospitals) in the Houston Area between 2016–18. Isolates were ribotyped by fluorescent PCR and susceptibility tested by agar dilution in accordance with CLSI standards. Vancomycin NS was defined by minimum inhibitory concentrations (MICs) > 2 mg/L. Genome assembly and analysis was completed through The Bacterial and Viral Bioinformatics Resource Center (BV-BRC) web resources.

Results

Overall, 36% (13/36) of the cohort was vancomycin NS. The most common ribotypes were F106 (n=13), F027 (n=10), and F014-020 (n=7). Median ARG abundance was 46 (IQR 45 – 49) and included genes encoding targeted and non-specific (i.e., encoding ABC transporters or efflux pumps) resistance. Specific antibiotics/classes targeted by identified ARGs included aminoglycosides, daptomycin, diaminopyrimidines, fluoroquinolones, fosfomycin, glycopeptides, isoniazid, lincosamides, macrolides, nitroimidazoles, oxazolidinones, rifamycins, streptogramins, and sulfonamides. Median ARG abundance did not differ between vancomycin NS (46.5 genes) and susceptible (46 genes) isolates and no differences in ARG patterns were observed. ARG abundance and patterns were similar amongst ribotypes.

Conclusion

C. difficile vancomycin non-susceptibility did not correlate with increased ARG abundance or any distinct ARG patterns. Future studies investigating interactions and implications of the C. difficile resistome on the microbiome and host are warranted.

Disclosures

Anne J. Gonzales-Luna, PharmD, BCIDP, Cidara Therapeutics: Grant/Research Support|Ferring Pharmaceuticals: Personal Fees|Paratek Pharmaceuticals: Grant/Research Support|Seres Therapeutics: Grant/Research Support Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|Ferring: Advisor/Consultant|Paratek: Grant/Research Support
2170. It takes two to tango: ß-lactam/ß-lactamase inhibitor combinations targeting metallo-ß-lactamase (MBL)- producing Klebsiella pneumoniae.
Authors: Kaur Jan Naseer , Klem Jack F , Singh Navaldeep , Holden Patricia N , Cha Raymond , Chen Liang , Kreiswirth Barry N , Smith Nicholas M , Tsuji Brian T
Published: November 2023

Background

The emergence of pan drug resistant (PDR) gram-negatives co-producing NDM-1 and CTX-M-15 calls for devising more efficient biocidal regimens. Also, understanding the salient transcriptomic and phenotypic changes that contribute to persistence which aid in pathogen survival is critical to therapeutic preparation in the clinical setting.

Methods

A 10-day hollow fiber infection model (HFIM) was utilized to simulate humanized β-lactam regimens involving imipenem (IMI) 1g q8h, aztreonam (ATM) 2g q8h, and ceftazidime/avibactam (CAZ/AVI) 2g/500mg alone and in 3-drug combination regimens against a PDR Klebsiella pneumonia isolate co-harboring blaNDM-1 and blaCMY-6, blaCTX-M-15 and blaSHV-2. Static time kills were performed to investigate the interplay between IMI and ATM. At 2h post drug exposure, total RNA was analyzed by qRT-PCR for the expression of pertinent genes. Glutaraldehyde-fixed samples were imaged using fluorescence and scanning electron microscopy.

Results

In HFIM, IMI contributed synergistically to the antimicrobial action as the average bacterial concentration between 30-120h was 2.1 log10 CFU/mL lower in ATM + CAZ/AVI + IMI than in ATM + CAZ/AVI (2.44 log10 CFU/mL vs. 4.54 log10 CFU/mL, respectively). Adding IMI to ATM+ CAZ/AVI also resulted in an enhanced post-antibiotic effect. Although ATM + IMI reduced bacterial counts by ≥4 log10 CFU/mL in 6h time kill assays, regrowth to the system carrying capacity of ∼8.5 log10 CFU/mL by 24h in all arms rendered these drugs ineffective. By 2h of treatment, ATM alone resulted in long filamentous cells whereas IMI resulted in significant populations of spheroplasts. ATM+IMI caused blebbing in the center of elongating filaments followed by a burst in spheroplast formation. qRT-PCR showed upregulation of spheroplast protein Y (spy) and penicillin binding proteins (pbp1, pbp2, pbp3) for all combinations involving IMI. However, pbp1, pbp3 and spy remained unchanged and pbp2 levels were downregulated by >25% in ATM monotherapy.

Conclusion

Overall, this PDR clinical isolate persisted in the presence of ATM + CAZ/AVI. The addition of IMI to target PBP2 in β-lactam combinations maximally suppressed the emergence of filamentous persisters and may be a promising strategy to prepare for increasing rates of gram-negative resistance.

Disclosures

All Authors: No reported disclosures