Inhibition of Podocytes DPP4 Activity Is a Potential Mechanism of Lobeliae Chinensis Herba in Treating Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease and has become a serious public health problem worldwide. Dipeptidyl peptidase-4 (DPP4) inhibitors, an emerging drug for the treatment of diabetes, have been found to have renoprotective effects in addition to glucose-lowering effects and therefore have the potential to be a treatment modality for DKD. Lobeliae Chinensis Herba (LCH), a traditional Chinese herb widely used in the treatment of diabetes, has recently been found to have a hypoglycaemic mechanism related to the inhibition of DPP4. Firstly, analysis of single-cell sequencing data from mouse kidneys in the National Center for Biotechnology Information (NCBI) database revealed that DPP4 was specifically upregulated in DKD podocytes and was associated with podocyte proliferation. Subsequently, the network pharmacology approach was applied to the screening of compounds. Twelve LCH active ingredients targeting DPP4 were extracted from the Traditional Chinese Medicine System Pharmacology (TCMSP) database. In addition, these 12 compounds and DPP4 were molecularly docked to predict the probability of them affecting DPP4 activity. In vitro, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin were demonstrated to retard podocyte proliferation by inhibiting DPP4 activity and were the top five compounds predicted by molecular docking to be the most likely to affect DPP4 activity. The half maximal inhibitory concentration (IC50) of the five compounds for DPP4 activity were as follows. Acacetin Log IC50 = −8.349, 95%CI (−9.266, −7.265), Diosmtrin Log IC50 = −8.419, 95%CI (−8.889, −7.950), Log IC50 = −8.349, 95%CI (−9.266, −7.265), Methyl rosmarinate Log IC50 = −8.415, 95%CI (−8.751, −8.085), Kaempferol Log IC50 = −8.297, 95%CI (−9.001, −7.615), Quercetin Log IC50 = −8.864, 95%CI (−9.107, −8.615). Finally, Quercetin, Methyl rosmarinate, Kaempferol, Diosmetin and Acacetin qualified for pharmacokinetic and drug similarity screening and have the potential to be the most promising oral agents for the treatment of DKD.

Fixed-Dose Combination of Dipeptidyl Peptidase-4 Inhibitors Plus Metformin in Patients with Type 2 Diabetes: A Review on Safety and Efficacy

There is a significant increase noted in the incidence and prevalence of Type 2 diabetes mellitus (T2DM). The global number of diabetic patients is projected by the International Diabetes Federation (IDF) to reach 552 million. T2DM disease has chronic and progressive nature. More than fifty percent of patients do not attain adequate glycemic control despite initial sufficient monotherapy. To maintain target glycated hemoglobin (HbA1c) levels (<7%), dose adjustment and adoption of several diabetes therapies become necessary in many cases. Compared to monotherapy, a fixed drug combination of oral agents and metformin has proven to be more efficacious to maintain levels of blood glucose and HbA1c. The combination of dipeptidyl peptidase-4 inhibitors (DDPIs) and metformin has been explicated to effectively decrease HbA1c to a relatively higher degree compared to the use of either agent individually. This combination addresses various pathophysiological processes involved in T2DM pathogenesis. Additionally, the concerned combination is safe and associated with a lower risk of hypoglycemia. Moreover, it is well-tolerated and prescribed as an easy-to-use single pill to improve patient compliance. This review provides an overview of the pharmacology, efficacy, and safety of fixed drug combinations of DDPIs and metformin according to current practice.

Survival Analysis on Time-To-Recovery of Diabetic Patients at Minlik Referral Hospital, Ethiopia: Retrospective Cohort Study

AimThe study aimed to determine the time to recovery of diabetic patients who have been treated in the hospital under follow-up. Subject and MethodsA retrospective cohort study design was carried out. The fast blood glucose level of diabetic patients who are under follow-up in the hospital was measured from 2016 to 2020. One thousand seven hundred diabetic patients were included in the study. Kaplan-Meier, Log-rank test, global test, Schoenfeld residuals, and Cox-PH model were used for statistical analysis.ResultsOut of the total of 1278 patients, 27.4% were censored (withdrawal from follow-up) and 72.6% recovered from the diabetic disease. For sex, the expected hazard is 1.322 times higher in males than female diabetic patients or there is a 32.2% increase in the expected hazard in males relative to female diabetic patients. For Spdrt, The expected hazard is 1.164 times higher in the patients who had taken leute than diabetic patients who took doanied. For regimen, the expected hazard is 1.495 times higher in the patients who had been treated by insulin agent only than diabetic patients who were treated by oral agents only ConclusionThe intensive-therapy regimen, Spdrt, and gender differences were statistically significant and critically contribute to the survival time to recovery of diabetic patients.

Real-World Treatment Patterns and Outcomes of Patients with Chronic Lymphocytic Leukemia (CLL) Receiving First-Line (1L) Therapy in the United States (US)

Background: There have been many advances in CLL treatments over the past decade, with a number of novel agents targeting molecular pathways within CLL cells receiving approval from the US Food and Drug Administration. Here, we assessed the evolution of molecular testing patterns, treatment patterns, and clinical outcomes over time in patients receiving 1L CLL treatment in a real-world US database. Methods: This was a retrospective cohort study using the Flatiron Health database, a longitudinal database comprising de-identified, patient-level, structured and unstructured data, curated via technology-enabled abstraction. During the study period, the de-identified data originated from approximately 280 cancer clinics (~800 sites of care) in the US. Patients aged 18 years and older who were diagnosed with CLL and initiated 1L treatment between December 2015 and December 2020 were selected. Participants who took part in a clinical trial in any line of therapy, or who had any other primary cancer diagnosis, were excluded. Baseline characteristics, including testing patterns, at initiation of 1L treatment were assessed using descriptive statistics. Treatment patterns and outcomes, such as time to next treatment or death (TTNTD), were analyzed. Kaplan-Meier analysis was used to estimate TTNTD. Results: Among 3654 patients with treatment-naive CLL who were selected from the de-identified database, the mean age at 1L treatment initiation was 70 years (range, 29-85); 64.3% of patients were male; 72.1% were White, 8.2% Black, 3.9% Hispanic/Latino, 1.0% Asian, and 14.9% were of other ethnicity/race. Approximately one-third (34.7%) of patients had Rai stage 0-I disease, 6.9% had stage II, 6.3% stage III, 11.5% stage IV, and 40.6% had undocumented Rai stage. Testing patterns: The majority of identified patients (3202/3654; 87.6%) had undergone cytogenetic testing, fluorescence in situ hybridization, or IGHV mutation testing. Compared with 2015-2016, testing rates were higher in 2019-2020 for chromosome 17p deletion (del(17p); 36.1% vs 45.7%, respectively; p&lt;0.001) and for IGHV mutation status (84.7% vs 89.2%, respectively; p=0.003). Overall, 11.0% of patients had del(17p). Of those tested for IGHV (1472/3654; 40.3%), 58.3% had unmutated IGHV. Treatment patterns: The 10 most commonly used 1L CLL treatments, which overall represented 91.8% of all 1L treatments, and their evolution over time, are reported in Table 1. Of the patients receiving these top 10 1L treatment regimens overall, 45.7% received regimens including novel targeted oral agents, 33.4% received chemo-immunotherapy (CIT), and 19.7% received anti-CD20 monotherapy. Evaluation of each 2-year period shows that treatment patterns for the top 10 1L treatment regimens shifted, with use of novel targeted oral agents increasing from 27.1% (2015-2016) to 63.8% (2019-2020) (p&lt;0.001), while use of CIT and chemotherapy decreased over time (Table 2). Approximately 30.0% (1088/3654) of 1L-treated patients went on to receive second-line treatments. Outcomes: Median TTNTD was 34.4 months for all patients receiving 1L CLL treatment, and 36.5 months for patients who received the 10 most common 1L treatments across the 6-year study period (n=3360). Median TTNTD was 47.0 months for patients who received novel targeted oral agents and 41.5 months for patients who received CIT (unadjusted p=0.16). When evaluating outcomes in patients with high-risk cytogenetics, median TTNTD was 29.1 months for patients with del(17p) and 37.2 months for those with unmutated IGHV, but was longer in those patients who received treatment with novel targeted oral agents (median TTNTD of 43.9 and 46.7 months, respectively; Table 3). Conclusions: This analysis provides the current state of 1L CLL testing and treatment patterns and outcomes in the US from 2015 to 2020. As expected, the use of novel targeted oral agents increased over time, with a corresponding increase in TTNTD. Clinical outcomes were improved in patients receiving novel targeted oral agents, both overall and in high-risk subgroups. Following on from this, a comparative study of TTNTD for novel oral agents versus CIT, and analyses of outcomes of different sequencing of therapies, will be conducted. Figure 1 Figure 1. Disclosures Mato: Nurix: Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; MSKCC: Current Employment; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genmab: Research Funding; LOXO: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ravelo: Genentech, Inc.: Current Employment; Roche Holdings: Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. To: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Schuldt: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; Johnson & Johnson: Divested equity in a private or publicly-traded company in the past 24 months. Biondo: Genentech, Inc.: Current Employment; Roche: Current holder of individual stocks in a privately-held company.

Successful Conversion and Implementation to Subcutaneous Daratumumab in Patients with Multiple Myeloma (MM) and Light Chain (AL) Amyloidosis

Introduction Intravenous (IV) daratumumab has become a standard in the treatment of MM and AL amyloidosis largely due to its significant clinical benefit. Due to the high risk of infusion-related reactions (IRRs) prolonged infusion times are required at time of treatment initiation. These lengthy administrations can limit clinic capacity, require split dose infusions, increase chair time, and decrease patient satisfaction. Fixed-dose subcutaneous (SC) formulation of daratumumab (daratumumab and hyaluronidase-fihj) was approved in 2020 for the treatment of MM and subsequently, AL amyloidosis in 2021. While landmark trials have demonstrated its efficacy, there is lack of consensus around the standardized pre-medications and post-injection monitoring times for SC daratumumab. We present real world evidence from a large academic center with adoption and standardization of SC formulation of daratumumab into clinical practice. Methods We evaluated all patients that received SC daratumumab for MM and/or AL amyloidosis at Boston Medical Center from June 1, 2020 to February 28, 2021. Baseline demographics were collected, including patient diagnosis, chemotherapy regimen, prior daratumumab administration details, and total doses of daratumumab received. Patients that were naïve to daratumumab, started their first dose as a SC injection. Patients were monitored for 30 minutes following the first SC dose and were pre-medicated with all oral agents: acetaminophen, dexamethasone, and diphenhydramine. Infusion chair time, improvement in clinic efficiency (using our standard infusion time of 90 minutes for IV daratumumab infusions after the 2nd dose), and safety were evaluated. Results A total of 41 patients were treated with SC daratumumab. Eighteen patients (44%) were switched from IV daratumumab to SC daratumumab. All other patients were naïve to SC daratumumab (n=23). All patients were monitored for 30 minutes after their first SC daratumumab dose only. In the absence of an ARR (administration-related reactions), patients were not monitored after subsequent injections. One patient had facial and neck swelling 2 days after administration of SC daratumumab (with no other symptoms) but resolved within 24 hours of an additional dose of dexamethasone and did not recur upon re-challenge of SC daratumumab. One patient experienced nausea following her first dose of SC daratumumab but it resolved without intervention. All patients received dexamethasone 20-40 mg (as anti-myeloma dose), acetaminophen 650 mg, and diphenhydramine 25-50 mg prior to the dose of SC daratumumab. Fourteen patients (24%) received montelukast 10 mg and 19 patients (46%) received famotidine 20-40 mg prior to the dose of SC daratumumab at provider discretion. Dexamethasone 4 mg daily for two days post-injection was not administered with SC formulation as was previously routine with the IV formulation. When analyzing the chair time saved by this standard monitoring protocol, a total of 478.8 hours of chair time were saved that were used for other patients in our practice (average of 11.7 hours saved per patient). Conclusion We report a successful conversion and adoption of SC daratumumab at our ambulatory hematology/oncology clinic. A standard 30-minute monitoring parameter can safely be implemented following the first SC daratumumab dose. Furthermore, less aggressive supportive medications can also be used. Integration of the SC formulation yielded significant chair time savings and may have the ability to create a more efficient clinic workflow. Figure 1 Figure 1. Disclosures Hughes: Rigel: Other: Advisory Board, Research Funding; Amgen: Speakers Bureau; Karyopharm: Other: Advisory Board, Speakers Bureau; Abbvie: Speakers Bureau. Sloan: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Stemline: Honoraria. Sanchorawala: Abbvie: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria.

Association of Insurance Type on Outpatient Copayments and Drug Utilization of Oral Multiple Myeloma Medications Via All-Claims Analysis, 2014-2018

Introduction Currently, there are three FDA-approved novel multiple myeloma (MM) oral agents commonly used in clinical practice in the United States: two immunomodulators (lenalidomide [len] and pomalidomide [pom]) and one proteasome inhibitor (ixazomib [ixa]). The financial burden faced by patients with MM on these drugs can be considerable due to increasing long-term survival and extended periods of continuous single agent maintenance or multidrug combination regimens. To better understand the financial burden associated with extended use of these medications, we sought to leverage a real-world, all-claims insurance database to examine the outpatient drug copayments, associated fill patterns, and duration of therapy of these MM oral agents, stratified by insurance type. We hypothesize that copayments associated with oral MM agents will comprise a major portion of the overall drug copayment per patient, and fill patterns and duration of therapy of these medications will vary across patients of different insurance types. Methods We utilized outpatient drug claims derived from the 2014-2018 IBM/Truven MarketScan Commercial, Medicare Advantage, and Medicaid all-claims databases and extracted all outpatient claims from patients who filled at least one prescription (≥28-day duration) for len, pom, or ixa. Annual outpatient medication copayment and number of outpatient scripts were calculated for each patient, both for oral MM agents only and all outpatient prescriptions. Copayments were normalized to the cost per annum. Multivariable linear regression was used to compare outcomes between patients of the three insurance types. Results From 2014-2018, we identified 10,750 patients on len, 2,355 patients on pom, and 794 patients on ixa. These included patients with commercial insurance (53.5%), Medicare Advantage (37.8%), and Medicaid (8.7%). The average adjusted annual copayment per patient of len was $445 for commercial, $480 for Medicare Advantage, and $48 for Medicaid (Table 1). Len copayment comprised of 77-83% of the total outpatient drug copayment per patient. For pom, adjusted copayments were $460 for commercial, $749 for Medicare Advantage, and $128 for Medicaid. Pom copayment comprised 54-90% of the total. For ixa, adjusted copayments were $584 for commercial, $448 for Medicare Advantage and $2 for Medicaid. Ixa copayment comprised 7-48% of the total. Patients with commercial insurance generally filled more scripts for oral MM agents per year (6 len, 4 pom, 5 ixa) compared to those with Medicare Advantage (5 len, 5 pom, 4 ixa) and Medicaid (4 len, 4 pom, 4 ixa) (Table 2). However, patients with commercial insurance filled fewer overall outpatient scripts per year (31-37) compared to Medicare Advantage (35-42) and Medicaid (40-52). Insurance type was associated with the number of scripts filled for len (p&lt;0.0001) and ixa (p=0.01) after adjustment for age, but not pom (p=0.14). Among patients on oral MM therapy for more than one year, insurance type was associated with time on therapy for len (828 days for commercial, 873 days for Medicare Advantage, and 791 days for Medicaid, p=0.0004) (Table 3). However, insurance type was not associated with time on therapy for pom (p=0.83) or ixa (p=0.11). Discussion Our results demonstrate that copayments for oral MM agents comprise the majority of total outpatient drug copayments for patients with MM, suggesting that the out-of-pocket costs of these agents may be a key driver of financial burden. In addition to differences observed in the oral MM drug copayments, insurance type was also associated with the number of scripts filled and time on therapy for patients taking len. Thus, this suggests insurance type is also linked to drug utilization patterns and may indicate a differential financial burden in patients with MM on chronic oral therapy. Reducing the cumulative impact of financial toxicity for patients with MM is an important consideration for prescribers, payors, and health systems to achieve optimal clinical outcomes. Although our current dataset lacks diagnostic and treatment data, further correlative studies incorporating care utilization data, including inpatient admissions and outpatient clinical visits, are in progress. Figure 1 Figure 1. Disclosures Pianko: Karyopharm: Honoraria.

Real-World Evidence on Shift in Treatment Practice and Adoption of Novel Agents for Patients with Chronic Lymphocytic Leukemia in the United States

Introduction: Clinical availability of highly effective novel agents (including Bruton tyrosine kinase [BTK] and B-cell lymphoma 2 [BCL-2] inhibitors) is rapidly altering the therapeutic landscape of chronic lymphocytic leukemia (CLL) necessitating a review of treatment guidelines. However, there is limited real-world data to validate if the availability of these novel agents has translated to a true shift in treatment paradigm for patients treated in the community. As the majority of CLL patients are treated in non-academic community-based settings, we investigated the clinical adoption trends of commercially available FDA approved novel agents for treatment of CLL patients. In addition, given that the COVID-19 pandemic led to major alteration in clinical oncology practices, we further studied if this contributed to an alteration in the selection of therapeutic agents resulting in changes of CLL treatment patterns and the utilization of novel agents in the real-world setting. Thus, the objectives of this study were to examine the utilization pattern of various CLL therapies, as well as evaluate the pattern of adoption of novel agents for treatment and the impact of COVID. Methods: A retrospective observational study was conducted using the Flatiron Health database that comprised EHR-derived de-identified data. Adult patients (≥18 years) with newly diagnosed CLL from January 2014 to May 2021, with no prior treatment and who were continuously enrolled for at least 6 months before and 3 months after the index date, defined as the first date of CLL/SLL diagnosis were included. Treatment regimens were classified into seven mutually exclusive categories: bendamustine-based chemotherapy, other chemotherapy, anti-CD20-based therapy, ibrutinib, idelalisib, acalabrutinib and venetoclax. Further treatment categorization included chemotherapy vs. targeted therapy, and traditional IV vs. novel oral agents. The impact of the pandemic was examined by comparing the pre- and post-COVID cohorts (defined as 15 months pre- and post- of March 1, 2021). Descriptive analyses were conducted to examine the frequency of use of treatment regimens by quarter in each year, line of therapy and between different age, gender, US geographical region, insurance status, and race/ethnicity subgroups. Multivariable regression was conducted to examine factors associated with the likelihood of adoption of novel and oral agents. Statistical significance was determined at a p-value of less than 0.05. Results: A total of 3,037 newly diagnosed CLL patients (median age =73) were included in the study. Over half were male (62.3%), white (74.6%) and commercially-insured (54.1%). Patients were primarily treated in community practices (92%). Overall, a significant trend in adoption of novel agents was observed throughout the years following their approval (Figure 1A). Across the evaluation period, a significant decrease in chemotherapy use was observed from 61.3% (quarter 1, 2014) to 20% (quarter 2, 2021) in favor of targeted therapy as first-line therapy (Figure 1B). In contrast, the utilization of novel oral agents (vs. traditional IV agents) for first-line therapy increased from 9.5% to 70.9% for the same period (Figure 1C). Similar trends were observed for second-line and third-line therapies. Encouragingly, this change in treatment patterns was adopted comparably in all sociodemographic subgroups with no evidence of disparity. While there was no statistically significant difference between the pre- and post-COVID treatment landscape, the adoption of target and novel oral agents has been more pronounced with the COVID pandemic. Conclusions: Results from real-world data suggest that there is a clear shift towards the adoption of novel therapies with preference given to targeted agents and oral therapies in the US since 2014. Further research examining real-world outcomes associated with treatment regimens are needed to inform decision makers. Figure 1 Figure 1. Disclosures Chanan-Khan: Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Ascentage: Research Funding; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BeiGene, Jansen, Ascentage: Honoraria; BieGene, Jansen, Ascentage: Consultancy. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Zimmerman: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment. Ailawadhi: Karyopharm: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Takeda: Consultancy; GSK: Consultancy, Research Funding; Xencor: Research Funding; Cellectar: Research Funding; Medimmune: Research Funding; Ascentage: Research Funding; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; BeiGene, Ltd.: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy.

1226. In Vitro Activity of Tebipenem and Comparators Against Enterobacterales Collected from Patients with Bloodstream Infections as Part of the 2019 Global STEWARD Surveillance Program

Background Bloodstream infections (BSI) are a significant cause of morbidity and mortality. Enterobacterales (ENT) are frequently implicated in BSI with an increase in organisms producing extended-spectrum β-lactamase (ESBL). This challenges a possible transition to current oral agents due to co-resistance. Carbapenems are active against ESBL-ENT and tebipenem (TBP) is a new oral carbapenem in clinical development. The aim of the study was to assess resistance (R) among BSI isolates and activity of TBP and comparators against ENT collected in a 2019 surveillance study. Methods 2612 ENT from BSI were centrally tested by reference broth microdilution. Isolates were from medical centers in the US, Europe (EU), Latin America (LA) and Asia Pacific (AP). MIC results were interpreted according to CLSI, including ESBL assignment. CRE were sequenced to identify carbapenemase genes. Results Among the ENT, non-susceptibility (NS) rates to ceftazidime, levofloxacin were 20.4 and 27.0%, respectively, and R to trimethoprim-sulfamethoxazole was 31.1%. NS rates for ertapenem (ETP) and MER were 4.9 and 2.7%, respectively. MIC90s for TBP, ETP and MER were 0.12, 0.12 and 0.06 µg/mL, respectively. The MIC90 for TBP was 0.06 µg/mL for ENT from the US and 0.12 µg/mL for isolates from EU, LA and AP. Escherichia coli (EC) was the most prevalent (52% of ENT isolates) and the MIC90 for TBP ranged from 0.015 µg/mL for isolates in the US/EU to 0.03 µg/mL for isolates in LA/AP. ESBL-EC ranged from 15.7% in US to 34.3% in LA. TBP was active against ESBL-EC with an MIC90 of 0.03 µg/mL. Klebsiella pneumoniae (KP) accounted for 22.7% of BSI caused by ENT and TBP MIC90 ranged from 0.06 µg/mL for KP in US to &gt;8 µg/mL in EU, LA and AP. MER-R KP ranged from 2.4% in US to 14.9% in LA. KPC-2, -3 and NDM were the most prevalent carbapenemases. TBP MIC90 values for MER-S ESBL KP in EU, LA and AP were ≤0.12 µg/mL. Conclusion TBP activity was similar to ETP and MER against ENT responsible for BSI. R to oral agents was compromised by ESBL co-resistance. TBP was among the most active agents against EC isolates and ESBL phenotypes. Among KP, TBP was more active against isolates from US where prevalence of CRE was lower than EU, LA and AP. TBP may be considered as an alternative oral option for BSI caused by non-CRE ESBL-producing ENT. Disclosures Ian A. Critchley, Ph.D., Spero Therapeutics (Employee, Shareholder) Nicole Cotroneo, Spero Therapeutics (Employee, Shareholder) Rodrigo E. Mendes, PhD, AbbVie (Research Grant or Support)AbbVie (formerly Allergan) (Research Grant or Support)Cipla Therapeutics (Research Grant or Support)Cipla USA Inc. (Research Grant or Support)ContraFect Corporation (Research Grant or Support)GlaxoSmithKline, LLC (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, LLC (Research Grant or Support)Nabriva Therapeutics (Research Grant or Support)Pfizer, Inc. (Research Grant or Support)Shionogi (Research Grant or Support)Spero Therapeutics (Research Grant or Support)

CDK4/6 Inhibitors: Paving the Way for HR-Positive, HER2-Negative Early Breast Cancer

Cyclin-dependent kinase (CDK) 4/6 inhibitors are revolutionizing care for patients with advanced and metastatic hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative (HER2–) breast cancer. These oral agents, often combined with other hormone-based therapy, have demonstrated considerable success in clinical trials and are used widely in oncology practices. CDK4/6 inhibitors are also being investigated for the treatment of early stage HR+, HER2– breast cancer. The addition of abemaciclib to adjuvant endocrine therapy improved invasive disease-free survival and distant relapse-free survival compared with endocrine therapy alone in patients with HR+, HER2–, node-positive, high-risk early breast cancer, and is now FDA-approved as adjuvant treatment in this setting. Here we review recent clinical data supporting the use of CDK4/6 inhibitors in both early and metastatic breast cancer. In addition, an expert faculty panel will discuss practical strategies to promote and improve adherence and side effect management in patients being treated with oral CDK4/6 inhibitors.

219. Outcomes with Low- vs. High-bioavailability Oral Antibiotics in Treatment of Uncomplicated Gram-Negative Bacteremia

Background High-bioavailability (HIGH-BIO) oral agents (i.e. trimethoprim-sulfamethoxazole, fluoroquinolones) are increasingly utilized for definitive treatment of uncomplicated gram-negative (UGN) bloodstream infections (BSI). Literature supports use of HIGH-BIO agents as step-down therapy, but few studies have assessed use of low-bioavailability (LOW-BIO) agents (i.e. beta-lactams). Increased recurrence of BSI has been associated with LOW-BIO agents; suboptimal dosing of beta-lactam agents may have impacted outcomes. Trials have not assessed whether high-dose beta-lactams (HD-BL) improve clinical outcomes over low-dose beta-lactams (LD-BL) for UGN BSI. Methods This retrospective cohort study conducted between December 2016 and December 2020 included adults with UGN BSI administered oral step-down therapy for at least 1/3rd the total antibiotic duration. The primary outcome was incidence of treatment failure of HIGH-BIO compared to LOW-BIO agents within 90 days of completing oral therapy. Treatment failure was a composite of all-cause mortality, recurrent BSI, reinfection of the primary site, or transition to IV antibiotics after initiating oral therapy. Secondary outcomes were incidence of treatment failure of HIGH-BIO compared to HD-BL agents, and of HD-BL compared to LD-BL agents. Results Of 225 patients, 67 (29.8%) received a HIGH-BIO and 158 (70.2%) a LOW-BIO agent; of those in the LOW-BIO arm 126 (79.7%) received a HD-BL. The most common source of BSI was urinary (202 [89.8%]); transition to oral therapy occurred after a mean of 5 ± 2.39 days. No difference in treatment failure was observed (8 [11.9%] HIGH-BIO vs. 25 [15.8%] LOW-BIO, P = 0.45). A numerically higher number of patients in the LOW-BIO arm had recurrent BSI (4 [2.5%] LOW-BIO vs. 0 [0%] HIGH-BIO, P = 0.18). No difference in treatment failure was observed between HIGH-BIO and HD-BL agents (8 [11.9%] vs. 20 [15.9%], P = 0.46), or HD-BL and LD-BL agents (20 [15.9%] vs. 5 [15.6%], P = 0.97). Conclusion No difference in treatment failure was observed between groups; further study is needed due to failure to reach statistical power. A numerical trend towards increased recurrence of BSI was observed with LOW-BIO agents. Beta-lactams may be reasonable for step-down therapy of UGN BSI if HIGH-BIO agents are contraindicated. Disclosures All Authors: No reported disclosures