bluuebunny/crossref_metadata_2025 huggingface dataset:
2500. An Audit of Hepatocellular Carcinoma Surveillance amongst Patients with Chronic Hepatitis B Attending an Irish Tertiary Centre
Authors: Heeney Aoife , Chianain Aine Ni , McNally Cora
Published: November 2023

Background

The association between chronic hepatitis B (CHB) and hepatocellular carcinoma (HCC) is well established, however it can be challenging to identify those who require surveillance. The European Association for the Study of the Liver (EASL) guidelines recommend 6-monthly liver ultrasound (US) as the optimal surveillance method and using the PAGE-B score for HCC risk stratification. This score offers good predictability for HCC whilst on nucleoside analogue therapy, and it also appears reliable in untreated patients. It has also been validated for individuals with HIV/HBV coinfection. We aimed to assess the compliance of an Irish tertiary hospital with the EASL guidelines for HCC surveillance.

Methods

We carried out a retrospective review of electronic medical records of patients with CHB attending the infectious diseases outpatient clinic in Beaumont Hospital, Dublin, Ireland.

Results

70 patients were included, of which 20 were co-infected with HIV. Of the 50 patients with CHB monoinfection, 4% (n=2) had cirrhosis and 20% (n=10) were on treatment. 98% (n=49) were undergoing surveillance with 90% undergoing 12-monthly US. We analysed each patient's PAGE-B score from their most recent clinic data and 6 (12%) were stratified as high risk, 24 (48%) as medium risk and 20 (40%) as low risk. Of those coinfected with HIV, 15% (n=3) patients had cirrhosis and all patients were on anti-viral therapy. 7 patients (35%) were undergoing HCC surveillance. PAGE-B scores stratified 5 patients (25%) as high risk, 10 (50%) as medium risk and 5 (25%) as low risk. [Table 1 and 2]

Conclusion

The majority of patients with CHB monoinfection are receiving HCC surveillance with annual US. Using the PAGE-B score we identified 40% that are low risk and for which regular surveillance may be deferred. Those who were stratified as medium or high risk would benefit from more frequent 6-monthly US. This audit highlights the benefit of risk stratification in the allocation of resources. There was a lack of surveillance in our coinfected population despite 15 patients (75%) being stratified as medium or high risk. This may be due to clinicians focusing on HIV-associated issues during clinic visits and highlights the importance of addressing both infections when reviewing these patients.

Disclosures

All Authors: No reported disclosures
2501. Trends in viral hepatitis and hepatocellular carcinoma in New York City, 2001–2018
Authors: Latham Ned H , Anger Holly , Bocour Angelica , Qiao Baozhen , Insaf Tabassum , McPherson Tristan D
Published: November 2023

Background

In New York City (NYC), an estimated 243,000 people live with chronic hepatitis B virus (HBV) infection and 86,000 people live with chronic hepatitis C virus (HCV) infection, representing 2.9% and 1% of the population, respectively. HBV and HCV can cause liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Early diagnosis improves HCC survival, and regular screening of people with HBV and other risk factors (e.g., family history of HCC or active liver inflammation) or HCV with cirrhosis is recommended. We aimed to describe recent trends in viral hepatitis and HCC in NYC.

Methods

We generated a retrospective cohort of NYC residents with HCC by matching New York State Cancer Registry data with NYC Health Department viral hepatitis surveillance data. We included all HCC cases diagnosed from 2001-2018 in the analyses, except those reported solely by Veterans Affairs hospitals or other state Cancer Registries. We defined people as having HBV and/or HCV if they met the Council for State and Territorial Epidemiologists’ probable or confirmed case definition before, or within 30 days of, their HCC diagnosis. We analyzed annual incidence of HCC stratified by viral hepatitis status (HBV, HCV, coinfection, neither), and the proportion of patients diagnosed with HCC at the local stage (vs. regional or distant stage).

Results

Between 2001–2018, 13,209 NYC residents were diagnosed with HCC; 2,456 (18.6%) had HBV, 5,379 (40.7%) had HCV, and 282 (2.1%) had HBV/HCV coinfection (Table 1). Incident HCC cases increased from 495 in 2001 to a peak of 878 cases in 2012 (Figure 1). The number of HCC cases with HBV or no viral hepatitis was relatively stable over the period, while HCC cases with HCV increased steadily until 2012, then declined slightly from 2016 to 2018. The proportion of HCC cases diagnosed at the local stage generally increased for people with HBV (48.3 to 60.7%), HCV (52.6% to 59.3%), and neither infection (41.4 to 57.6%).Figure 1.Trends in viral hepatitis status of incident hepatocellular carcinoma (HCC) cases among New York City residents, 2001–2018. HBV = hepatitis B virus HCV = hepatitis C virus HCC = hepatocellular carcinomaTable 1.Characteristics of people diagnosed with hepatocellular carcinoma with and without viral hepatitis in New York City, 2001–2018.IQR = interquartile range HCC = hepatocellular carcinoma Due to rounding, category percentages do not all sum to 100.

Conclusion

Recent declines in HCC among NYC residents reflect declines in HCC cases with HCV. Despite increases in the proportion of HCC cases diagnosed at the local stage, opportunities to improve screening remain. Additional analyses accounting for antiviral treatment, cirrhosis, alcohol intake, and mortality, would assist in further informing HCC prevention efforts.

Disclosures

All Authors: No reported disclosures
139. Clinical Predictors of a Positive MPox PCR: A Framework for Diagnostic Stewardship
Authors: Gonzales Adrienne M , Yeh Rose , Rostane ikram , Ratliff Hunter , Wanger Audrey , Ostrosky-Zeichner Luis
Published: November 2023

Background

In July 2022, an outbreak of MPox was reported in the United States as part of a world-wide health emergency. Healthcare settings in the US started to see possible cases, and the public health and clinical diagnostics infrastructure was quickly overwhelmed. As the concept of diagnostic stewardship is becoming increasingly more important, we sought to identify clinical information obtainable at presentation that would predict a positive MPox PCR in order to streamline testing and optimize resource utilization.

Table 1

RR and diagnostic performance for single and combined clinical factors resulting in a positive MPox PCR

Methods

The charts of 146 patients presenting for MPox testing in a large healthcare system in Texas in July and August 2022 were reviewed to identify clinical factors upon presentation that would correlate with a positive lesion PCR.

Results

49.3% of patients tested positive. The mean (SD) age of patients was 31.9 (8.41) years. The mean (SD) time of symptoms was 5.47 (5.08) days. The mean (SD) time from last sexual encounter was 17.6 (11.01) days. Table 1 shows the RR and diagnostic performance for each clinical factor resulting in a positive MPox PCR as well as the RR for those with 2, 3, and 4 combined high risk clinical factors.

Conclusion

Male gender, non-heterosexual sexual orientation, recent sexual encounter, painful lesions, contact with a known MPox case, systemic symptoms, and shorter symptom duration less than or equal to 6 days increased the risk of a positive Mpox PCR result and may be used to prioritize testing in a resource constrained environment. Patients presenting with a combination of 2, 3, and 4 risk factors further increased the likelihood of a positive test. Risk factors can be used for diagnostic stewardship in MPox testing. Further research will focus on creation and prospective validation of clinical prediction rules.

Disclosures

Luis Ostrosky-Zeichner, MD, FACP, FIDSA, FSHEA, FECMM, CMQ, Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Advisor/Consultant|F2G: Advisor/Consultant|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|GSK: Advisor/Consultant|Melinta: Advisor/Consultant|NIH: Grant/Research Support|Pfizer: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Pulmocide: Grant/Research Support|Scynexis: Grant/Research Support|T2 Biosystems: Grant/Research Support|Viracor: Advisor/Consultant
2503. Re-engagement in Care for Patients with Positive Hepatitis C Virus Antibody Test: A Descriptive Study at a Large University Hospital
Authors: Mendoza Denise , Ryan Keenan L , Deming Paulina , Cabos Heather , Bacon Kristin , Jakeman Bernadette
Published: November 2023

Background

An HCV micro-elimination project conducted at the University of New Mexico Hospital (UNMH) found a large number of patients with a positive HCV antibody test but no confirmatory HCV RNA test. The purpose of this study was to 1) conduct a telemedicine intervention to re-engage patients with a positive HCV antibody test and no confirmatory HCV RNA test and 2) investigate patient understanding of HCV testing and treatment and identify barriers that impeded patient access to care.

Methods

Through the hospital electronic medical record system, patients with positive HCV antibody tests were identified at UNMH in Albuquerque, NM, USA. Patients were eligible for study inclusion if they were aged > 18 years and had a positive HCV antibody test with no confirmatory HCV RNA documented between January 2019-December 2020. Eligible patients were contacted by phone and asked to participate in a survey on questions addressing socio-demographics, patient awareness of HCV antibody results, knowledge of HCV, and knowledge of current oral HCV treatment options. At survey completion, patients were offered HCV confirmatory testing. Study investigators followed-up with patients who chose to obtain confirmatory testing to provide results and, if appropriate, to refer patients for HCV treatment. Data were analyzed using descriptive statistics to describe the study population. Re-engagement was measured based on the completion of the HCV RNA.

Methods

Inclusion/Exclusion Criteria

Results

Study investigators attempted to contact 454 patients. From the screened charts, 49% were not reached, 5% passed away, 6% declined, and 4% agreed to participate in the survey. The median age was 51 years. 60% were male and 55% were white. 82% had an annual income of < $35k. All but one of the participants were aware of their HCV antibody test, but many were not aware of chronicity of the virus and available oral treatments. 15 patients had received outside follow up testing and/or treatment. 5 participants were successfully re-engaged in care and received confirmatory testing.

Screening Table

Patient Characteristics

Conclusion

This study highlights the complexity of reaching this patient population to re-engage patients in care for HCV, which is likely due to a number of previously identified socioeconomic factors. This further supports HCV programs that engage patients in care prior to hospital discharge.

Disclosures

Keenan L. Ryan, PharmD, PhC, PharmCon: Honoraria Paulina Deming, PharmD, Gilead: Advisor/Consultant
2507. Sex and race disparities in hepatocellular carcinoma surveillance in patients with chronic hepatitis B: a single center retrospective review
Authors: Reiche William , Cooper Stephen , Destache Christopher , Sidhu Suhail , Schutte Bryce , Keirns Darby , mac Elezabeth , Ng Ian , Buaisha Haitam , Velagapudi Manasa
Published: November 2023

Background

The management of patients with chronic hepatitis B (CHB) is complex and involves interdisciplinary care across multiple medical specialties. As a result of this complexity, patients with CHB often do not receive adequate monitoring including HCC surveillance with abdominal ultrasonography (AUS). Previous studies have identified multiple factors associated with decreased HCC surveillance. We aimed to study race and sex disparities in HCC surveillance in patients with CHB during the COVID-19 pandemic.

Methods

We performed a single center retrospective cohort study of patients treated for CHB between January 2018 and January 2022 in Gastroenterology and Infectious Diseases clinics at our institution. HCC surveillance trends for both sexes were further stratified by 6-month time intervals throughout the study period to compare surveillance during the COVID-19 surge at our region and after the surge. The COVID-19 pandemic surge was defined as time 1/1/2020-6/30/2021. Differences between sex and race were evaluated using the chi-square test, Fisher's exact test, and continuous variables were analyzed using analysis of variance (ANOVA).

Results

A total of 223 adult patient records between January 2018 and January 2022 were evaluated. In total 37% females were adequately screened for HCC in any of the 6-month time frames compared to 26% for males, p >0.05. During the COVID-19 surge, surveillance rates were reduced in both males and females; however, men had significantly reduced HCC screening compared to women (men 38% compared to women 47%, P = 0.011, Figure 1). When comparing COVID-19 HCC screening, stratified by race, 20% Asians, 34% African Americans, and 22% Caucasians were screened by AUS, P = 0.069(Figure 2).

Patient Demographics

ID, infectious diseases clinic; GI, gastroenterology clinic; SD, standard deviation

Conclusion

Males received significantly less HCC surveillance compared to females. These differences continued during the COVID-19 pandemic surge. Obtaining appropriate surveillance is important and identifying disparities enables treating physicians to work on measures to mitigate them.

Disclosures

All Authors: No reported disclosures
2511. Screening for Hepatitis B Virus (HBV) and Tuberculosis (TB) Infection among Non-U.S.-Born Adults from High HBV and TB Burden Countries
Authors: Skarbinski Jacek , Ni Yuching , Wick Jenna M , Chitnis Amit S , Krueger Amy L , Jaganath Devan , Wong Robert J , Halmer Nicole
Published: November 2023

Background

Hepatitis B virus (HBV) infection and tuberculosis (TB) infection both disproportionately affect non-U.S.–born persons from countries with hepatitis B surface antigen (HBsAg) seroprevalence ≥2% or TB incidence rates ≥20/100,000 population. Early identification and treatment of chronic HBV and TB infection are critical to reduce morbidity and mortality, but little is known about HBV and TB screening among non-U.S.–born persons in the United States.

Methods

In a cross-sectional study using electronic health record data, we assessed HBV and TB infection screening practices among Kaiser Permanente Northern California eligible members aged ≥18 years born in countries with intermediate to high burdens of both HBV and TB infection. HBV screening was defined as testing for HBV surface antigen and HBV core antibody. TB infection screening was defined as testing with interferon gamma release assay or tuberculin skin test. We calculated the proportion of individuals from intermediate and high HBV-TB burden countries who had HBV or TB infection screening and the proportion of patients positive for HBV or TB infection.

Results

Of 498,339 non-U.S.–born adults, 275,708 (55.3%) were born in intermediate or high HBV-TB burden countries. Most patients were aged ≥50 years (65.3%) and 23.5% had diabetes. Among persons born in intermediate or high HBV-TB burden countries, 67.1% were screened for HBV infection, 29.4% were screened for TB infection, and only 23.7% were screened for both HBV and TB infection. Among all persons born in intermediate or high HBV-TB burden countries (both screened and unscreened), 3.7% had HBV infection and 10.1% had TB infection. Among 231,431 persons born in intermediate or high HBV-TB burden countries without current or prior HBV infection, 72.9% had received at least one HBV vaccine dose.

Conclusion

Among non-U.S.–born adults from intermediate or high HBV-TB burden countries, we found low screening proportions, intermediate prevalence of chronic HBV infection and high prevalence of TB infection. Given the large population of persons from intermediate or high HBV-TB burden countries in Kaiser Permanente Northern California, screening for both infections at the same time could improve early diagnosis and treatment for both conditions.

Disclosures

Jacek Skarbinski, MD, Genentech: Grant/Research Support|Gilead Sciences: Grant/Research Support Robert J. Wong, MD, MS, Gilead Sciences: Grant/Research Support
2512. A Decade in Review: An Analysis of the Qualified Infectious Disease Product (QIDP) Designation
Authors: Atillasoy Cem , Elmansy Lina , Gourlias Panagiotis
Published: November 2023

Background

The development of new antibiotics is a critical public health need, as antibiotic-resistant infections are responsible for tens of thousands of deaths each year in the U.S. In response, the QIDP (Qualified Infectious Disease Product) designation was established by the FDA under the Generating Antibiotic Incentives Now (GAIN) Act in 2012. The program incentivizes the development of new drugs to treat serious or life-threatening infections caused by bacteria or fungi that are resistant to existing treatments. These incentives include priority review and 5 additional years of market exclusivity for drugs that receive QIDP designation and are subsequently approved by the FDA.

Methods

We analyzed the FDA Database entitled, “Compilation of CDER New Molecular Entity (NME) Drug and New Biologic Approvals” for antimicrobial therapies approved after 2012. Antimicrobial therapies were defined as antibiotics and antifungals, excluding antivirals and antiparasitics which are ineligible for QIDP. We compared the status of the QIDP designation in drugs that gained FDA approval over two 5-year periods (2013-2017 vs. 2018-2022). We also analyzed the types of infections and pathogens targeted by these drugs.

Results

Since the GAIN Act in 2012, there have been 25 antimicrobial therapies approved, 20 with the QIDP designation (Table 1). 9 drugs with QIDP status were approved (out of 13 antimicrobials) from 2013-2017; whereas 2018-2022 had 11 drugs approved with QIDP status (out of 12 antimicrobials) (Figure 1). There was no significant difference in QIDP approvals over the two periods (69% vs. 92%, p=0.32).

Of the 20 drugs approved with the QIDP designation, 9 are indicated to treat genitourinary infections, 6 to treat gastrointestinal infections, 5 to treat skin infections, 3 to treat pulmonary infections and only 1 to treat systemic infections. Furthermore, 15 of the drugs targeted bacterial pathogens, 4 targeted fungal pathogens and 1 targeted mycobacteria (Table 2).

Conclusion

Our findings indicate that the QIDP designation has been moderately effective in generating renewed interest in the development of antibiotics. Additional strategies are needed to encourage continued infectious disease R&D efforts, especially around areas of unmet need such as systemic infection and fungal pathogens.

Disclosures

All Authors: No reported disclosures
2514. Single Ascending Dose Safety, Tolerability, and Pharmacokinetics of Subcutaneous and Intramuscular CD388, a Novel Long-acting Drug-Fc Conjugate for Universal Prevention of Seasonal and Pandemic Influenza
Authors: Flanagan Shawn , Ong Voon , Baguet Tristan , Rojas Roxana E , Wang Sy-Shi , Equils Ozlem
Published: November 2023

Background

CD388 is a novel antiviral drug-Fc conjugate (DFC) designed to deliver universal prevention of seasonal and pandemic influenza. Nonclinical studies have shown CD388 was effective prophylactically against a wide range of seasonal and pandemic influenza A and B strains in lethal and nonlethal mouse models of infection.

Methods

The design of the ongoing blinded CD388 First in Human study, which is being conducted in healthy subjects is shown in Figure 1. CD388 for injection (100 mg/mL) was administered by intramuscular (IM) or subcutaneous (SQ) routes of administration. Single dose pharmacokinetics were determined for subjects in the 50 and 150 mg cohorts of each dosing route at protocol specified nominal time points; alias subject numbers were used to maintain blind. Plasma CD388 concentrations were determined for subjects randomized to receive CD388 using a validated hybrid immunoassay LC-MS method with lower limit of quantitation (LLOQ) of 0.1 µg/mL.

Results

CD388 appeared to be well absorbed by IM or SQ routes of administration with maximum plasma concentrations (Tmax) appearing from 2 to 13 days post dose, and quantifiable concentrations ( >LLOQ) lasting for several weeks to months (Figures 2 to 4). Mean apparent half-life of elimination was ∼ 50 days. Increases in CD388 exposures were approximately dose proportional for both routes (Figures 2 to 4).

No dose limiting local or systemic safety concerns were noted from review of ongoing blinded safety data and the study is proceeding at doses higher than those reported herein.

Conclusion

Plasma concentrations of CD388, were similar following intramuscular or subcutaneous routes of administration and were sustained. No safety concerns have been noted in this ongoing study.

Disclosures

Shawn Flanagan, PhD, Cidara Therapeutics: Salaried Employee|Cidara Therapeutics: Stocks/Bonds Voon Ong, Executive Director, Cidara Therapeutics: Stocks/Bonds Tristan Baguet, PharmD, Johnson & Johnson: Employee Roxana E. Rojas, M.D., Ph.D., Janssen: Employee|Janssen: Stocks/Bonds Sy-Shi Wang, Ph.D., Janssen Pharmaceutical: Employee Ozlem Equils, MD, Cidara Therapeutics: Employee|Cidara Therapeutics: Stocks/Bonds
2533. Cerebrospinal Fluid Penetration of Cefazolin and Flucloxacillin in Children
Authors: Boast Alison , Lei Alice , Harwood Kiera , Gonis Gena , Di Carlo Amanda , Daley Andrew J , Ungerer Jacobus , McWhinney Brett , Curtis Nigel , Gwee Amanda
Published: November 2023

Background

Effective treatment of methicillin-susceptible Staphylococcus aureus meningitis requires antimicrobial penetration into the CSF. Anti-staphylococcal penicillins, including flucloxacillin, are generally recommended as first-line treatment. However, some evidence suggests that the first-generation cephalosporin, cefazolin, may be an appropriate alternative. We investigated the CSF concentration of cefazolin and flucloxacillin in children.

Methods

CSF samples from children aged 0-18 years treated with cefazolin or flucloxacillin were collected when there was sample remaining after diagnostic tests were completed. Unbound antibiotic concentrations of cefazolin and flucloxacillin were measured.

Results

Overall, 222 CSF samples were collected from 163 children, median age 12 months (range 0.0-17.5 years). Of these, 157 were collected while the antibiotic was at steady state. For cefazolin, children ≤1 year had a higher median CSF concentration compared with those >1 year (1.8 versus 0.5 mg/L, p< 0.001), whereas for flucloxacillin the concentration was similar between the two age groups (0.2 versus 0.1 mg/L, p=0.9). In infants aged ≥ 1 month to 1 year, the CSF concentration of both antibiotics was higher in those with pleocytosis (WCC >5 x106/L) than those without (flucloxacillin 0.2 versus 0.065 mg/L, cefazolin 5.6 versus 1.06 mg/L). Notably, only those aged ≤1 year receiving cefazolin (7/12; 58%) achieved steady state CSF concentrations above the CLSI breakpoint for sensitive S. aureus (MIC ≤2 mg/L).

Conclusion

CSF penetration of cefazolin was higher in younger infants and for both antibiotics was higher in those with pleocytosis. In most children, the CSF concentrations in the CSF for either cefazolin or flucloxacillin were not above the S. aureus MIC.

Disclosures

All Authors: No reported disclosures
2536. Comparing the activity of broad-spectrum beta-lactams in combination with aminoglycosides and aztreonam/avibactam against 8 VIM-producing CRE
Authors: Clark Justin A , Burgess David
Published: November 2023

Background

Treatment of infections caused by CRE often involves beta-lactam-containing combination therapy, either with a beta-lactamase inhibitor or an agent from a different antimicrobial class. We sought to investigate the activity of several beta-lactam combinations against 8 VIM-producing CRE cultured from patients at our academic medical center using a time-kill assay.

Methods

Broth microdilution was utilized to obtain the MICs. TK was performed in duplicate with samples taken 0, 4, 8, and 24 hours after initial inoculation. During each time point, samples were automatically spiral plated onto Mueller Hinton agar plates and incubated for 16-24 hours at 37 oC before colonies were enumerated to estimate bacterial density (CFU/mL). Antimicrobials tested included meropenem 16 μg/mL, cefepime 32 μg/mL, piperacillin/tazobactam 64/4 μg/mL, amikacin 4 μg/mL, plazomicin 4 μg/mL, and aztreonam/avibactam 32/4 μg/mL. Average bacterial density reduction after 24 hours was the outcome of interest.

Results

Meropenem and plazomicin alone achieved bactericidal or bacteriostatic activity in at least a single time-kill experiment for all isolates except for meropenem against one isolate. Aztreonam/avibactam and meropenem with either amikacin or plazomicin achieved bactericidal activity by 4 hours which sustained until 24 hours except for a single isolate in which meropenem/plazomicin only achieved bacteriostatic activity. These combinations were the most active with average bacterial density decreases of 3.86, 3.89, and 3.64 log10reductions, respectively. Cefepime or piperacillin/tazobactam combined with plazomicin minimally improved the average bacterial inocula reduction compared to plazomicin monotherapy. When combined with amikacin, cefepime and piperacillin/tazobactam achieved inconsistent bactericidal activity after 24 hours, though cefepime on average led to a bacterial reduction > 2 log10 CFU/mL lower than piperacillin/tazobactam.

Conclusion

Against 8 clinical VIM-producing K. pneumoniae and E. cloacae, beta-lactam combination therapy achieved rapid and sustained bactericidal activity. Further investigation is necessary to rationally guide the use of these combination therapies against CRE.

Disclosures

All Authors: No reported disclosures
2538. The Impact of Rifampicin on Blood Pressure in Patients Receiving Nifedipine: A Retrospective Study
Authors: Eljaaly Khalid
Published: November 2023

Background

No comparative study has been published to date to evaluate the impact of drug-drug interaction (DDI) between rifampin (CYP3A4 inducer) and nifedipine on clinical outcomes. The aim of this study was to investigate the change in systolic blood pressure (SBP) after rifampin initiation in hypertensive patients who were receiving oral nifedipine.

Methods

This retrospective cohort study was conducted at King Abdulaziz University Hospital. We included hospitalized adults ≥18 years who were started on rifampin while they were receiving oral nifedipine for hypertension. Patients with uncontrolled hypertension (baseline SBP of >140 mmHg) and those receiving beta-blockers were excluded. The study outcomes were SBP changes by day 8 after rifampin initiation, which were compared by Chi-squared test.

Results

A total of 16 patients were included. The median maximum increase in SBP from baseline after starting rifampin was 24 [17.75 - 29] mmHg. The median SBP did not increase significantly on the second day (135 [128.5-141.5]; P=0.147) but the increases were significant on the following days. The median SBP was 146.5 [140.5-154.25] (P=0.002) on the third day, 142.5 [132.75-160.5] (P=0.009) on the fourth day, 149.5 [136-159.75] (P=0.005) on the fifth day, 146.5 [134.25-159.5] (P=0.012) on the sixth day, 149 [143.25-154.5] (P=0.007) on the seventh day, 151.5 [143.75-163] (P=0.007) on the eighth day.

Conclusion

Initiation of rifampin in hypertensive nifedipine-treated patients was associated with a statistically and clinically significant increase in SBP starting from day 3 of rifampin. This supports the need to avoid nifedipine use in patients taking rifampin.

Disclosures

Khalid Eljaaly, PharmD, MS, BCPS, BCIDP, FCCP, Reckitt Benckiser Healthcare International Ltd, UK: Member of the Global Respiratory Infection Partnership, supported by unrestricted educational grant from Reckitt Benckiser Healthcare Ltd
2547. Targeting penicillin-binding protein 2 (PBP2) to treat metallo-beta-lactamase (MBL)-producing Klebsiella pneumoniae: Mecillinam as an American Ninja Warrior
Authors: Klem Jack F , Candidate Pharm D , Kaur Jan Naseer , Smith Nicholas M , Chen Al , Holden Patricia N , Bulitta Jürgen B , Tsuji Brian T
Published: November 2023

Background

‘Nightmare’ MBL gram-negatives resistant to nearly all antibiotics have emerged in the clinical setting and are a cause for concern. Here, we assessed the role of targeted PBP2 binding using mecillinam (MEC), which is currently available in other countries and has high affinity for PBP2, as an adjuvant to established β-lactam regimens to combat pan drug resistance.

Methods

Klebsiella pneumoniae harboring blaNDM-1, blaCMY-6, blaCTX-M-15, and blaSHV-2 was exposed to an array of therapeutic drug regimens in a Hollow Fiber Infection Model (HFIM) at a starting inoculum of ∼107 CFU/mL over 168h. These arms included MEC monotherapy (2hPI Q8H, target Cmax,ss = 32 ug/mL) in addition to combination regimens that contained aztreonam (ATM) (2g 2hPI Q8H) + ceftazidime/avibactam (CAZ/AVI) (2g/0.5g 2hPI Q8H) ± MEC (2hPI Q8H, target Cmax,ss = 32 ug/mL). All drugs were discontinued at 168h, after which populations were assessed for regrowth for 48h. Samples were also collected, fixed, and imaged under a scanning electron microscope (SEM, Carl Zeiss Auriga).

Results

The MEC monotherapy arm regrew to carrying capacity (∼1010 CFU/mL) in 24h whereas combination arms demonstrated bactericidal activity throughout the duration of drug treatment. While 24h killing rates were comparable between the two combination arms, 168h counts were ∼3.0 log10 CFU/mL lower in ATM + CAZ/AVI + MEC than in ATM + CAZ/AVI (102.90 CFU/mL vs. 105.92 CFU/mL, respectively). Both combination arms recovered following drug discontinuation; however, this recovery was delayed in ATM + CAZ/AVI + MEC as was supported by a ∼6.5 log10 CFU/mL difference in 192h counts (109.51 CFU/mL in ATM + CAZ/AVI vs. 102.98 CFU/mL in ATM + CAZ/AVI + MEC). 192h SEMs supported this observation as rods predominated in the ATM + CAZ/AVI sample whereas more debris/fewer cells were apparent in the ATM + CAZ/AVI + MEC sample. Spheroplasts were observed throughout drug treatment in all samples treated with MEC.

Conclusion

The targeted PBP2 binding capacity of MEC may be a promising adjuvant to β-lactam/β-lactamase inhibitor combinations. Non-traditional β-lactam strategies that enhance the existing antibiotics may be of paramount importance for clinicians to combat MBL gram negative pan drug resistance.

Disclosures

All Authors: No reported disclosures
2548. Pharmacokinetic Analysis of Co-Administering Doravirine, Tenofovir Disoproxil Fumarate, Estradiol, and Spironolactone
Authors: Lam Kevin , Zhan Tingting , Kraft Walter , Lam Edwin
Published: November 2023

Background

Despite the availability of doravirine (DOR) as a fixed-dose combination product and its favorable safety profile, transgender women (TGW) are less likely to adhere to antiretroviral therapy over concerns of drug interactions with feminizing hormone therapy. This study evaluated the effect of DOR (given as a single dose containing lamivudine (3TC) and tenofovir disoproxil fumarate (TDF)) and TDF on the pharmacokinetics (PK) of estradiol (E2) and spironolactone and vice versa.

Methods

A phase I, three-period crossover, bi-directional drug interaction study was conducted. Healthy volunteers self-identified as TGW were randomized 1:1 into 2 sequences containing treatment A (DOR/3TC/TDF 100 mg/300 mg/300 mg as a single dose), treatment B (E2 4 mg twice daily, spironolactone 200 mg twice daily, and placebo for one day), and treatment C (single dose of DOR/3TC/TDF 100 mg/300 mg/300 mg, E2 4 mg twice daily, and spironolactone 200 mg twice daily for one day). Plasma DOR, TDF, E2, and testosterone were collected for PK evaluation. DOR, TDF, and E2 PK parameters were computed via a non-compartmental analysis and compared using a paired student’s t-test. Safety and tolerability were evaluated throughout the study.

Study Flow

Results

Out of 8 participants enrolled in the study, 6 completed the study. Geometric mean ratios (co-administration vs. without co-administration) and 90% confidence intervals for DOR, TDF, and E2 area under the concentration-time curve from zero to last measured concentration (AUC0-last), maximum concentration (Cmax), and concentration at 24 hours (C24) are reported in Table 1. Log-transformed DOR, TDF, and E2 PK parameters computed with and without co-administration were not statistically significant (p > 0.05).

Statistical Analysis of PK Parameters for Doravirine, Tenofovir Disoproxil Fumarate, and Estradiol

Conclusion

These results demonstrate that a clinically significant interaction is not observed involving the use of feminizing hormones on DOR/TDF PK. Similarly, no observed impact on estradiol PK and testosterone is anticipated following use of DOR/TDF/3TC. DOR/TDF administered with and without E2 and spironolactone was generally well tolerated.

This work was supported by an Investigator Studies Program grant provided by Merck & Co., Inc. MISP59198. The opinions expressed are those of the authors and do not necessarily represent those of Merck & Co., Inc.

Disclosures

All Authors: No reported disclosures
2554. What’s Weight Got to Do with It? Prospective Pharmacokinetic/Pharmacodynamic Evaluation of Fixed-Dose Daptomycin
Authors: Olney Katie B , Thomas Jenni , Pai Manjunath P , Burgess Donna R , Olney William , Bruning Rebecca , Griffith Kamron Amir , Casaus Danielle , Crance Elizabeth , Burgess David
Published: November 2023

Background

As daptomycin (DAP) CL does not scale proportionally with weight, fixed-dose DAP has been proposed to optimize efficacy and mitigate toxicity. This study evaluated systemic exposure of a fixed dose (750 mg) of DAP in patients with Staphylococcus aureus infections.

Methods

Adult non-ICU patients with CrCl ≥ 30 mL/min admitted to our academic medical center warranting DAP for a S. aureus infection were eligible for enrollment. DAP 750 mg was infused over 30 minutes every 24 hours. At steady state, concentrations were obtained pre-dose (0.5 hours) and 1, 12, and 24 hours after the start of infusion. Concentrations were measured using a validated LC-MS assay. Pharmacokinetic (PK) analysis was performed using first-order equations and stratified by weight: low (< 65 kg), normal (65-85 kg), and high ( > 85 kg). Therapeutic AUC24 (≥ 666 mg*hr/L) and elevated trough (Cmin > 24.3 mg/L) were the efficacy and safety targets, respectively.

Results

Overall, 22 patients (6 low weight, 8 normal weight, 8 high weight) were enrolled with no differences observed in baseline characteristics (median [IQR] age 49 [42.2, 56.5], CrCl 111 mL/min [79, 134]). PK parameters (median [IQR]) did not differ by weight with Vd 9.9 L [6.3, 17.2], Ke 0.078 h-1 [0.046, 0.098], CL 0.87 L/h [0.47, 1.34], AUC24 861 mg*hr/L [538, 1541], and Cmin 10.5 mg/L [7.3, 29.9]. Therapeutic AUC24 was achieved in 14/22 (64%) and elevated Cmin occurred in 7/22 (32%), with no differences seen among weight groups. However, differences were noted between males (n=10) and females (n=12) with significantly higher CL (median [IQR]) noted in males (1.26 L/h [0.92, 1.48]) vs. females (0.49 L/h [0.37, 0.86]) (p=0.027). Hence, median [IQR] AUC24 was significantly lower in males at 594 mg*hr/L [454, 736] vs. 1513 mg*hr/L [856, 1879] in females (p=0.021). Therapeutic AUC24 was achieved in 40% of males versus 83% of females, while elevated Cmin was seen in 20% of males and 32% of females.

Conclusion

DAP PK and exposure (AUC24 and Cmin) was not impacted by weight. These results support fixed, rather than weight-based, dosing of DAP in non-ICU patients with normal renal function. Notably, gender differences were observed with males having significantly higher CL, likely warranting higher doses of DAP to ensure optimal exposure.

Disclosures

Katie B. Olney, PharmD, BCIDP, The Society of Infectious Diseases Pharmacists (SIDP): Grant/Research Support
2558. Association of Vancomycin-Induced Acute Kidney Injury with Trough Versus AUC Monitoring in Patients Receiving Extended Durations of Therapy
Authors: Pitcock C Tyler , Wallace Katie L , Schadler Aric , Burgess David , Burgess Donna R , Cotner Sarah , VanHoose Jeremy , Gregory Eric
Published: November 2023

Background

Vancomycin (VAN) therapy is associated with an increased risk of AKI. Previous studies suggest that AUC monitoring reduces the risk of AKI, but literature is lacking in patients receiving longer durations of VAN therapy. This study assessed the clinical impact of AUC monitoring on patients receiving at least 14 days of VAN.

Methods

Adult inpatients at our academic medical center that received ≥ 14 days of VAN with levels obtained during a 4-year period were included in this analysis. Our primary outcome was the incidence of AKI between trough monitoring and AUC monitoring groups using the KDIGO change in serum creatinine from baseline criteria. Secondary outcomes included inpatient mortality, inpatient LOS, and ICU LOS. Multivariable logistic regression models were performed for AKI incidence and inpatient mortality.

Results

A total of 582 patients were included. The majority of patients were male (58.2%) and Caucasian (94.3%). The median duration of VAN therapy was 23 days (IQR, 16-39). Patients within the trough monitoring group had a higher incidence of AKI compared to the AUC monitoring group (45.6% vs. 28.4%, p< 0.001). In each KDIGO stage, there was a higher incidence of AKI in the trough monitoring group compared to the AUC monitoring group (Stage 1: 22.0% vs. 15.9%, Stage 2: 10.7% vs. 7.6%, and Stage 3: 12.9% vs. 4.9%, p< 0.001). Logistic regression analysis showed AUC monitoring was associated with a 54% lower incidence of AKI (OR 0.46, 95% CI [0.31-0.69]). ICU LOS within the trough monitoring group was longer compared to the AUC monitoring group (13 days [6-24] vs. 10 days [3-19], p=0.008). All-cause inpatient mortality was numerically higher in the trough monitoring group (12.9% vs. 8.3%, p=0.078). In the second multivariable regression analysis, AUC monitoring was not a significant predictor of mortality, but patients with AKI were five times more likely to die (OR 5.00, 95% CI [2.40-10.46], p< 0.001).

Conclusion

AUC monitoring can reduce the risk of AKI in patients receiving ≥ 14 days of VAN and indirectly reduce the risk of inpatient mortality. Consideration should be given to implementing AUC monitoring as a standard of practice.

Disclosures

All Authors: No reported disclosures
2559. Antibiotic-induced Bartter-like syndrome - A Systematic Review
Authors: Priyadarshi Megha , Paul Saurav Sekhar , Soneja Manish
Published: November 2023

Background

Bartter syndrome encompasses salt-losing tubulopathies characterized by hypokalemia, hypochloremic metabolic alkalosis, and hyperreninemic hyperaldosteronism with normal blood pressure. Acquired Bartter or Bartter-like syndrome (BLS) is commonly associated with the use of diuretics and antibiotics such as capreomycin, netilmicin, colistin, and amphotericin B. This systematic review was done to understand the time of occurrence of Bartter syndrome post-inciting drug and gain knowledge regarding its progression and management.

Methods

We searched PubMed, Google Scholar, Embase, medRxiv, and bioRxiv databases for articles published from 1986 to March 2022 using the keywords "Antibiotic," "Bartter Syndrome," "Pseudobartter Syndrome," and "Bartter-like." Studies that reported cases of BLS in adults or children with confirmation of the inciting drug were included. We excluded studies that did not provide sufficient details of the clinical presentation and outcome.

Results

We identified 31 studies, comprising 43 cases of BLS. The mean age of the patients was 41.1 years (range: 25–57 years), and 65.1% were female. The most common antimicrobial class associated with BLS was aminoglycosides (65.1%), followed by the polymyxin group. The most common antimicrobial was Gentamicin (41.8%), followed by Colistin (32.5%), Streptomycin, and Capreomycin (6.9% each). Hypokalemia(100%), metabolic alkalosis(97.2%), hypocalcemia(92.5%), and hypomagnesemia(100%) were reported in almost all patients. The median time of onset after exposure to the inciting agent was 10 days (range 7–18 days), and the median time for resolution after stopping the drug was 14 days (range 7–31 days). There was a complete resolution of the symptoms following discontinuation in all cases.

Demographic and baseline characteristics of the patients

Prevalence of electrolyte, acid-base disorder, and urinary electrolyte abnormalities

Laboratory parameters among the reported cases

Conclusion

BLS is a rare but potentially reversible complication of various antimicrobials, most commonly aminoglycosides. The diagnosis requires a high index of suspicion and a careful review of the drug history. The prognosis is favorable, with a complete reversal of the state after drug discontinuation.

Disclosures

All Authors: No reported disclosures
145. Tracheal Aspirate Order Indications and Associated Culture Results in Mechanically Ventilated Children
Authors: Jelic Monika , Weber Matthew J , Birkholz Meghan C , Dowell Elaine , Hamilton Stacey , Jung Sarah A , Baker Christopher D , Parker Sarah K , Dominguez Samuel R
Published: November 2023

Background

Tracheal aspirates (TAs) are collected on mechanically ventilated patients to aid in diagnosis of tracheitis or ventilator associated pneumonia. Accuracy of TA cultures to diagnose lower respiratory tract infections is low, limited by normal respiratory flora contamination, making interpretation difficult. To aid diagnostic stewardship efforts, we analyzed TA order indications to better understand why TA cultures were ordered and which indications were associated with a clinically significant culture result.

Methods

Order indications for TA specimens were implemented in Sept. 2021 at Children’s Hospital Colorado. At least one indication was required at the time of order placement, Table 1. We extracted all TA orders from Sept. 2021 to Aug. 2022, as well as demographics, collection department, and Gram stain/culture results.

Results

1,439 tracheal aspirate specimens were ordered for 496 unique patients. 34% were collected in the Emergency Department (ED), 22% in the Neonatal Intensive Care Unit (NICU), and 20% in the Pediatric Intensive Care Unit (PICU; Table 1). The two most common order indications were increase in secretions (37%) and increase in ventilator support (36%). 296 (22%) cultures grew 1 or 2 predominant organisms, with the most common indication being increased secretions; 57% of these cultures grew respiratory pathogens. Overall, 42% of cultures grew normal respiratory flora and 12% had no growth. For cultures with no growth and those with no organisms on Gram stain, the most common indication was increase in ventilator support. For all order indications, 50% or more grew normal respiratory flora with abnormal chest imaging and fever having the most cultures with 1 or 2 predominant organisms.

Conclusion

The majority of TAs are collected in the ED, NICU or PICU. The most common order indications were increase in secretions or increase in ventilator support. The most common order indication that was noted in actionable cultures (1 or 2 predominant organisms) was increased secretions, though order indication was not predictive. These results have informed potential Gram stain rejection criteria to improve diagnostic yield for clinically relevant pathogen detection.

Disclosures

Sarah A. Jung, PhD, Abbott Molecular Inc: Research support|DiaSorin Molecular: Research|Karius: Advisor/Consultant|Karius: Industry talks at two conferences Samuel R. Dominguez, MD, PhD, Biofire Diagnostics: Advisor/Consultant|Biofire Diagnostics: Grant/Research Support|Cobio Diagnostics: Board Member|Karius: Advisor/Consultant|Pfizer: Grant/Research Support
2571. Posaconazole DRT in Children; Time to Bring Out the Pill Crusher?
Authors: Weerdenburg Heather L , Gwee Amanda , Haeusler Gabrielle , Osowicki Joshua , Boast Alison
Published: November 2023

Background

Posaconazole, a broad-spectrum triazole antifungal, is licenced for prophylaxis and treatment of invasive fungal infections (IFI). Young children who are unable to swallow tablets or those with enteral tubes are routinely prescribed oral suspension. However, this formulation has poor bioavailability and despite appropriate dosing, often results in subtherapeutic concentrations. In contrast, the delayed release tablet (DRT) has excellent bioavailability irrespective of gastric pH resulting in reliable absorption and attainment of therapeutic exposure. Several adult case series have reported the achievement of therapeutic posaconazole concentrations by crushing DRT. We investigated the attainment of therapeutic posaconazole concentrations with crushed DRT.

Methods

Case series of children receiving posaconazole DRT via enteral tube between September 2022 to April 2023. Each 100mg DRT was crushed in ∼10ml of sterile water followed by a flush of ∼10ml - 20mL to avoid blocking the tube. Tablets were not given with food. Therapeutic trough serum concentrations were defined as ≥ 0.7mg/L (prophylaxis) and ≥ 1mg/L (treatment).

Results

Four children, aged 4 to 14 years, received crushed posaconazole DRT (treatment; n=3, prophylaxis; n=1). The median initial dose was 10 mg/kg/d (range 5 -11). All children achieved target concentrations, however, two children receiving posaconazole for treatment of IFI required a dose increase prior to achieving therapeutic concentrations. No toxicities were reported. The switch to posaconazole DRT facilitated earlier hospital discharge for 2 patients.

Posaconazole Trough Levels For IFI Treatment

Conclusion

Our case series demonstrates that therapeutic concentrations can be achieved when crushed poscaonzole DRT is administered via enteral tube. This formulation allowed the discontinuation of IV formulations, facilitating earlier patient discharge.

Disclosures

All Authors: No reported disclosures