scholarly journals mTOR inhibitors reduce enteropathy, intestinal bleeding and colectomy rate in juvenile polyposis of infancy due to PTEN-BMPR1A deletion syndrome

2021 ◽  
Author(s):  
Henry Taylor ◽  
Dilay Yerlioglu ◽  
Claudia Phen ◽  
Antje Ballauff ◽  
Natalia Nedelkopoulou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Mtor Inhibitor ◽  
Cohort Analysis ◽  
Mtor Inhibitors ◽  
Juvenile Polyposis ◽  
Deletion Syndrome ◽  
Intestinal Bleeding ◽  
Chromosome 10 ◽  
Mtor Inhibition ◽  
Early Therapy

Abstract Background Ultrarare genetic disorders can provide proof of concept for efficacy of targeted therapeutics and reveal pathogenic mechanisms relevant to more common conditions. Juvenile polyposis of infancy (JPI) is caused by microdeletions in chromosome 10 that result in haploinsufficiency of two tumor suppressor genes: phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and bone morphogenetic protein receptor, type IA (BMPR1A). Loss of PTEN and BMPR1A results in a much more severe phenotype then deletion of either gene alone, with infantile onset pan-enteric polyposis and a high mortality rate. No effective pharmacological therapy exists. Methods A multi-center cohort analysis was performed to characterize phenotype and investigate the therapeutic effect of mTOR inhibition (adverse events, disease progression, time to colectomy, and mortality) in patients with JPI. Results Among 25 JPI patients identified (mean age of onset 13 months), seven received mTOR inhibitors (Everolimus n = 2 or Sirolimus n = 5). Treatment with an mTOR inhibitor reduced the risk of colectomy (hazard ratio 0.27, 95% CI 0.07–0.954, p = 0.042) and resulted in significant improvements in serum albumin level (mean increase 16.3 g/L, p = 0.0003) and hemoglobin (mean increase 2.68 g/dL, p = 0.0077). Long-term mTOR inhibitor treatment was well tolerated over an accumulated follow-up time of 29.8 patient years. No serious adverse events were reported. Conclusion Early therapy with mTOR inhibitors offers effective, pathway-specific, personalized treatment for patients with JPI. Inhibition of the PI3K-AKT–mTOR pathway mitigates the detrimental synergistic effects of combined PTEN-BMPR1A deletion. This is the first effective pharmacological treatment identified for a hamartomatous polyposis syndrome.

Activity of single-agent bevacizumab (B) in patients with metastatic renal cell carcinoma (RCC) previously treated with VEGF- and mTOR-based therapies.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 435-435
Author(s):  
Andrew J. Armstrong ◽  
James D. Turnbull ◽  
Julien Cobert ◽  
Tracy Jaffe ◽  
Michael Roger Harrison ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitor ◽  
Single Agent ◽  
Progression Free Survival ◽  
Mtor Inhibitors ◽  
Mtor Inhibition ◽  
Grade 3

435 Background: Given a lack of clinical information on therapeutic efficacy of agents following progression after vascular endothelial growth factor (VEGF) tyrosine kinase inhibition (TKI) and mammalian target of rapamycin (mTOR) inhibition in metastatic renal cell carcinoma (mRCC), we investigated the activity of single agent bevacizumab (B) in this setting. Methods: We conducted a retrospective analysis of single agent B-treated patients with mRCC in the second/third line setting, and identified 21 subjects who met inclusion criteria. The primary endpoint was progression-free survival (PFS). Baseline characteristics, survival, response efficacy outcomes, and toxicities were assessed and summarized. Results: 21 patients (15 women/6 men) were treated with B at a dose of 5 mg/kg/week, dosed q2-3 weeks. Median age was 63, 80% were white, 14% black; 80% had clear cell histology. Median time from diagnosis to B therapy was 3 years (range 1-18); 100% had prior VEGF TKI therapy; 43% had prior mTOR inhibitor; 43% had prior IFN and 19% prior IL-2; median number of prior therapies was 3 (range 1-7); 100% were considered Motzer intermediate risk. Median PFS on B for all subjects was 4.4 mo (95% CI 2.8-9.6) and median OS was 19.4 mo (95% CI 9.9-NR) from start of B therapy. ORR was 2 CR/PR (9.5%), 11 SD (52%), 5 PD, 3 NE. For subjects treated with prior VEGF and mTOR inhibitors, median PFS and OS were 4.4/13.2 mo. Toxicities were as expected and severe adverse events included grade 3-4 fatigue (6), grade 3-4 dehydration (5), and grade 4 failure to thrive (2), grade 4 constipation (2), and grade 3 muscle weakness (2). Conclusions: Single agent B therapy has acceptable toxicity and moderate disease stabilizing activity in selected patients with mRCC who have failed prior VEGF TKI and mTOR inhibitor therapy, and suggests a benefit to continued ongoing VEGF inhibition. Further prospective study of B alone, in combination with mTOR inhibition, or with alternative targeted agents is warranted.

scholarly journals mTOR Inhibitors for the Treatment of Severe Congenital Hyperinsulinism: Perspectives on Limited Therapeutic Success

2016 ◽  
Vol 101 (12) ◽  
pp. 4719-4729 ◽  
Author(s):  
Marie Szymanowski ◽  
Maria Salomon Estebanez ◽  
Raja Padidela ◽  
Bing Han ◽  
Karolina Mosinska ◽  
...  
Keyword(s):  
Glycemic Control ◽  
Medical Therapy ◽  
Mtor Inhibitor ◽  
Pancreatic Insufficiency ◽  
Safety Information ◽  
Mtor Inhibitors ◽  
Mtor Signaling ◽  
Congenital Hyperinsulinism ◽  
Mtor Inhibition ◽  
Fasting Tolerance

Context: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in neonates and infants. In medically unresponsive CHI, subtotal pancreatectomy is performed to achieve euglycemia with consequent diabetes in later life. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been reported to obviate the need for pancreatectomy, but experience is limited. Objective: We have investigated the efficacy and adverse effect profile of mTOR inhibitors in the treatment of severe CHI. Design, Setting, and Patients: This was an observational review of 10 severe CHI patients treated with mTOR inhibitors, in France and the United Kingdom, with the intention of achieving glycemic control without pancreatectomy. Safety information was recorded. Main Outcome Measure(s): We examined whether mTOR inhibitors achieved glycemic control, fasting tolerance, and weaning of supportive medical therapy. Results: mTOR inhibition achieved euglycemia, fasting tolerance, and reduced medical therapy in only three patients (30%). Triglyceride levels were elevated in five patients (50%). One child required a blood transfusion for anemia, four had stomatitis, two had sepsis, one developed varicella zoster, and two patients developed gut dysmotility in association with exocrine pancreatic insufficiency. In silico analysis of transcriptome arrays from CHI patients revealed no significant association between mTOR signaling and disease. Pancreatic tissue from two patients who did not respond to sirolimus showed no reduction in cell proliferation, further suggesting that mTOR signaling did not down-regulate proliferation in the CHI pancreas. Conclusion: mTOR inhibitor treatment is associated with very limited success and must be used with caution in children with severe CHI.

Cellular and molecular effects of the mTOR inhibitor everolimus

2015 ◽  
Vol 129 (10) ◽  
pp. 895-914 ◽  
Author(s):  
Uttara Saran ◽  
Michelangelo Foti ◽  
Jean-François Dufour
Keyword(s):  
Mtor Inhibitor ◽  
Mtor Inhibitors ◽  
Cancer Therapies ◽  
Breast Cancers ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Molecular Effects ◽  
Mtor Complex 1

mTOR (mechanistic target of rapamycin) functions as the central regulator for cell proliferation, growth and survival. Up-regulation of proteins regulating mTOR, as well as its downstream targets, has been reported in various cancers. This has promoted the development of anti-cancer therapies targeting mTOR, namely fungal macrolide rapamycin, a naturally occurring mTOR inhibitor, and its analogues (rapalogues). One such rapalogue, everolimus, has been approved in the clinical treatment of renal and breast cancers. Although results have demonstrated that these mTOR inhibitors are effective in attenuating cell growth of cancer cells under in vitro and in vivo conditions, subsequent sporadic response to rapalogues therapy in clinical trials has promoted researchers to look further into the complex understanding of the dynamics of mTOR regulation in the tumour environment. Limitations of these rapalogues include the sensitivity of tumour subsets to mTOR inhibition. Additionally, it is well known that rapamycin and its rapalogues mediate their effects by inhibiting mTORC (mTOR complex) 1, with limited or no effect on mTORC2 activity. The present review summarizes the pre-clinical, clinical and recent discoveries, with emphasis on the cellular and molecular effects of everolimus in cancer therapy.

Comparision of Dual PI-3K/mTOR Inhibitors with mTOR Inhibitors Using a Pre-Clinical Model of Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3258-3258
Author(s):  
Jacky Wong ◽  
Robert Welschinger ◽  
Rana Baraz ◽  
Jocelyn Weiss ◽  
Ken Bradstock ◽  
...  
Keyword(s):  
Cell Death ◽  
Mtor Inhibitor ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Mtor Inhibitors ◽  
Mtor Inhibition ◽  
Induce Cell Death ◽  
Dual Kinase Inhibitors ◽  
Mtor Signalling

Abstract Abstract 3258 ALL cells are highly dependent on bone marrow stromal support for in vitro proliferation and survival. The major regulators of patient-derived ALL cell growth and survival convey their proliferative and survival signals through the phosphoinositide 3-kinase (PI-3K) pathway. It has been recently demonstrated that signalling through PI-3K and AKT is the most important pathway for the proliferative responses of ALL cells to CXCL12, the chemokine predominantly responsible for stromal dependent growth of ALL cells. In addition, inhibition of the mTOR signalling molecule downstream of PI3K with RAD001 has been shown to inhibit proliferation and induce cell death. Although PI-3K and mTOR have similar and overlapping functions, mTOR can be activated independently of PI-3K, and proliferation and survival can be stimulated by PI-3K in an mTOR independent manner. Therefore combining PI-3K and mTOR inhibition is likely to be advantageous over inhibition of either kinase alone, suggesting disruption of PI-3K/AKT/mTOR signalling will provide a new approach for the treatment of ALL. We investigated the dual kinase inhibitors BEZ235 and BGT226. Here, we demonstrate that PI-3K and mTOR inhibition with the dual kinase inhibitor BEZ235 significantly inhibits ALL proliferation in vitro, with IC50 values in the range of 7–20nM, indicating a 3 log greater potency in comparison to the mTOR inhibitor RAD001. The ability to induce cell death differed between the dual mTOR and PI-3K inhibitors, with BGT226 potently inducing cell death at 1.6μM, but more than 16μM of BEZ235 was required to kill ALL cells, with a combination of autophagy and apoptosis being detected. While cell death was induced with higher concentrations of BEZ235 than needed to inhibit proliferation, clonogenic assays revealed a major decrease in the survival capacity of cells exposed to the agent. We also demonstrate the activity of these dual kinase inhibitors in a NOD/SCID xenograft model of human ALL with significantly prolonged survival of mice. The potential synergy of dual kinase inhibitors with conventional chemotherapy drugs and in mTOR inhibitor resistant cases remains to be studied. Dual kinase inhibitors may offer an improved therapeutic index through reduced toxicity over mTOR inhibitors, and potentially reduce the risk of development of resistance to kinase inhibition. Disclosures: No relevant conflicts of interest to declare.

scholarly journals mTOR in Viral Hepatitis and Hepatocellular Carcinoma: Function and Treatment

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Zhuo Wang ◽  
Wei Jin ◽  
Hongchuan Jin ◽  
Xian Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Viral Hepatitis ◽  
Mtor Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Virus Hepatitis ◽  
Standard Chemotherapy ◽  
Mtor Inhibition ◽  
Promising Strategy ◽  
Common Cancer

As the fifth most common cancer in men and the eighth most common cancer in women, hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths worldwide, with standard chemotherapy and radiation being minimally effective in prolonging survival. Virus hepatitis, particularly HBV and HCV infection is the most prominent risk factor for HCC development. Mammalian target of rapamycin (mTOR) pathway is activated in viral hepatitis and HCC. mTOR inhibitors have been tested successfully in clinical trials for their antineoplastic potency and well tolerability. Treatment with mTOR inhibitor alone or in combination with cytotoxic drugs or targeted therapy drug scan significantly reduces HCC growth and improves clinical outcome, indicating that mTOR inhibition is a promising strategy for the clinical management of HCC.

Phase I Study of Novel Prodrug Dual PI3K/mTOR Inhibitor SF1126 In B-Cell Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1783-1783 ◽  
Author(s):  
Joseph R Garlich ◽  
Michael D Becker ◽  
Candace F Shelton ◽  
Wenqing Qi ◽  
Xiaobing Liu ◽  
...  
Keyword(s):  
Phase I ◽  
B Cell ◽  
Research Funding ◽  
Phase I Study ◽  
Mtor Inhibitor ◽  
International Workshop ◽  
Mtor Inhibitors ◽  
B Cell Malignancies ◽  
Mtor Inhibition ◽  
Over Time

Abstract Abstract 1783 Background: The PI3K/Akt/mTOR signaling pathway is an attractive target to inhibit for cancer therapy because it is altered in many cancers and is vital to essential biological processes. While inhibition of specific PI3K isoforms, such as δ, has demonstrated efficacy in B-cell malignancies, recent studies suggest that inhibition of all Class IA isoforms (α, β, and δ) is essential to produce maximal inhibition of cell proliferation and to induce apoptosis. For example, the pan PI3K inhibitor LY294002 has been shown to inhibit both the viability and chemotaxis of chronic lymphocytic leukemia (CLL) B-cells, whereas a PI3K δ inhibitor did not. Dual PI3K and mTOR inhibition is also expected to offer a therapeutic advantage, as several mTOR inhibitors have demonstrated promising activity in B-cell malignancies, including the mobilization of CLL cells from tissue sites into the circulation that could enhance the cytotoxicity of other agents. Objectives: The role of PI3K in a wide range of normal biologic processes raises potential safety concerns about dual inhibition of mTOR and all PI3K Class I isoforms. The objective of this Phase I study is to demonstrate that SF1126 can overcome these concerns by accumulating preferentially in tumor tissue to both maximize efficacy and minimize toxicity. SF1126 is a peptidic prodrug that converts to LY294002, one of the most widely studied dual PI3K/mTOR inhibitors. LY294002 is conjugated to an Arg-Gly-Asp (RGD) peptide via a cleavable linker to form SF1126, which has improved properties for clinical use. As a prodrug with improved solubility and site selectivity due to targeting of RGD-recognizing integrin receptors, SF1126 opened up a new avenue for the clinical development of LY294002. Furthermore, the fact that proliferation of CLL cells requires stromal support mediated through cytokines and adhesion molecules (eg, integrins) provides additional biological rationale for testing a RGD-targeted agent as a treatment for CLL. Methods: Based on translational studies demonstrating that LY294002 induces apoptosis in CLL cells and sensitize CLL cells to cytotoxic drugs, patients with CLL and other B-cell malignancies will be enrolled on this expanded Phase I trial at the maximum administered dose of SF1126 (1110 mg/m2) as determined by 47 patients treated to date in dose-escalation studies. SF1126 will be administered intravenously over 90-minutes on days 1 and 4 weekly in cycles of 4 weeks. Patients with CLL will be assessed using the International Workshop on CLL (IWCLL) criteria and patients with indolent non-Hodgkin's lymphoma (NHL) or mantle cell lymphoma (MCL) will be assessed using the International Workshop Group (IWG) criteria. Correlative pharmacodynamic studies will also be conducted to evaluate the potential inhibition of PI3K in tumor cells from patients enrolled in this trial. Results: At the maximum administered dose of 1110 mg/m2, SF1126 appears to be well tolerated and demonstrates activity in relapsed and refractory CLL patients treated to date in this ongoing Phase I study. Similar to the tumor flare reaction (TFR) demonstrated in CLL patients treated with immune-modulating agents, such as lenalidomide, two patients treated with SF1126 experienced TFR during the cycle one, day 1–4 time period. TFR has been postulated to be associated with a drug-induced, immune-mediated anti-tumor response and is manifested as an acute onset of swelling of involved lymph nodes that is not associated with disease progression. Time course analysis by flow cytometry of isolated lymphocytes from the first two CLL patients treated demonstrate consistent increases in late apoptosis over time relative to baseline following the first dose of SF1126. Western blot analyses of isolated lymphocytes from the first CLL patient treated demonstrate decreased pAKT (473) signaling and increased PARP cleavage over time relative to baseline. One CLL patient with a 17p deletion genotype demonstrated clinical activity as indicated by stable disease and significant lymph node decreases accompanied by an increases in absolute lymphocyte count (ALC) as seen with the mTOR inhibitor everolimus. The trial continues to enroll patients and updated results from this study will be presented. In view of SF1126's ability to mobilize CLL cells into the circulation, combination studies with synergistic agents that are effective against circulating CLL cells are also being planned. Disclosures: Garlich: Semafore Pharmaceuticals: Employment, Patents & Royalties. Becker:Semafore Pharmaceuticals: Consultancy, Patents & Royalties. Shelton:Semafore Pharmaceuticals: Consultancy. Qi:Seamfore Pharmaceuticals: Research Funding. Liu:Semafore Pharmaceuticals: Research Funding. Cooke:Semafore Pharmaceuticals: Research Funding. Mahadevan:semafore pharmaceuticals: Research Funding.

Phase II trial of the oral mTOR inhibitor everolimus (RAD001) for patients with relapsed or refractory lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8055-8055 ◽  
Author(s):  
P. B. Johnston ◽  
S. M. Ansell ◽  
J. P. Colgan ◽  
T. M. Habermann ◽  
D. J. Inwards ◽  
...  
Keyword(s):  
Phase Ii ◽  
Mtor Inhibitor ◽  
Mtor Inhibitors ◽  
Cell Transplant ◽  
Mtor Inhibition ◽  
Treatment Regimens ◽  
Common Grade ◽  
Group 3 ◽  
Grade 3 ◽  
Group 1

8055 Background: mTOR inhibition with intravenous temsirolimus (Wyeth Pharmaceuticals) has been associated with responses in mantle cell lymphoma (J Clin Oncol 23;5347, 2005) as well as other lymphomas (Blood 108 (11) 2483; 2006). This phase II study tested the oral mTOR inhibitor everolimus (RAD001, Novartis Pharmaceuticals) in three simultaneous two-stage phase II lymphoma studies - aggressive (group 1), indolent (group 2), or uncommon (group 3). The goals were to learn the toxicity profile and to assess the anti-tumor response. Planned interim analysis for groups 1 and 3 have been completed and are the subject of this report. Methods: Patients (pts) received 10 mg PO daily for each 28 day cycle (up to 12) and restaged after 2, 6, and 12 cycles. The primary endpoint is the confirmed response rate, including CR, CRu or PR. 12 pts were enrolled in stage 1 of each study. At least 1 success in 12 is required to proceed to stage 2, to a total of 37 pts. Overall, the treatment will be considered promising if 4 or more successes are observed in all 37 pts in each group. Results: The median age of the 12 pts in group 1 was 68.5 yrs (range: 53–80), with a median of 3 (range, 1–15) prior therapies. Four pts had a prior stem cell transplant (SCT). Pts completed a median of 7 (range, 1–12) cycles of therapy. 6 confirmed responses have been achieved (1 CR, 5 PR), meeting the overall criteria for promising results in this study. Common grade 3 adverse events (AEs) include thrombocytopenia (3 pts) and anemia (2 pts). For group 3, the median age was 49 yrs (range, 27–78), with a median of 7 (range, 1–13) prior therapies and 6 pts had a prior SCT. Pts have completed a median of 6.5 cycles (range, 1–11). 5 confirmed responses have been achieved (5 PR), meeting the criteria for this regimen to be considered promising. Of these 5 patients, 3 had HD, 1 T-cell NHL, and 1 had macroglobulinemia. Common grade 3 AEs include anemia (3 pts) and thrombocytopenia (2 pts). No grade 4 AEs were reported. Conclusions: Oral everolimus has activity in a spectrum of lymphomas with acceptable toxicity. The responses observed in both group 1 and group 3 met the criteria to continue accrual. These results provide the rationale for additional studies with this novel class of agents and to integrate mTOR inhibitors into salvage treatment regimens. No significant financial relationships to disclose.

scholarly journals The Association of Intraoperative driving pressure with postoperative pulmonary complications in open versus closed abdominal surgery patients – a posthoc propensity score–weighted cohort analysis of the LAS VEGAS study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Guido Mazzinari ◽  
◽  
Ary Serpa Neto ◽  
Sabrine N. T. Hemmes ◽  
Goran Hedenstierna ◽  
...  
Keyword(s):  
Propensity Score ◽  
Adverse Events ◽  
Abdominal Surgery ◽  
Las Vegas ◽  
Cohort Analysis ◽  
Risk Difference ◽  
Pulmonary Complications ◽  
Driving Pressure ◽  
Postoperative Pulmonary Complications ◽  
Open Abdominal Surgery

Abstract Background It is uncertain whether the association of the intraoperative driving pressure (ΔP) with postoperative pulmonary complications (PPCs) depends on the surgical approach during abdominal surgery. Our primary objective was to determine and compare the association of time–weighted average ΔP (ΔPTW) with PPCs. We also tested the association of ΔPTW with intraoperative adverse events. Methods Posthoc retrospective propensity score–weighted cohort analysis of patients undergoing open or closed abdominal surgery in the ‘Local ASsessment of Ventilatory management during General Anaesthesia for Surgery’ (LAS VEGAS) study, that included patients in 146 hospitals across 29 countries. The primary endpoint was a composite of PPCs. The secondary endpoint was a composite of intraoperative adverse events. Results The analysis included 1128 and 906 patients undergoing open or closed abdominal surgery, respectively. The PPC rate was 5%. ΔP was lower in open abdominal surgery patients, but ΔPTW was not different between groups. The association of ΔPTW with PPCs was significant in both groups and had a higher risk ratio in closed compared to open abdominal surgery patients (1.11 [95%CI 1.10 to 1.20], P <  0.001 versus 1.05 [95%CI 1.05 to 1.05], P <  0.001; risk difference 0.05 [95%CI 0.04 to 0.06], P <  0.001). The association of ΔPTW with intraoperative adverse events was also significant in both groups but had higher odds ratio in closed compared to open abdominal surgery patients (1.13 [95%CI 1.12– to 1.14], P <  0.001 versus 1.07 [95%CI 1.05 to 1.10], P <  0.001; risk difference 0.05 [95%CI 0.030.07], P <  0.001). Conclusions ΔP is associated with PPC and intraoperative adverse events in abdominal surgery, both in open and closed abdominal surgery. Trial registration LAS VEGAS was registered at clinicaltrials.gov (trial identifier NCT01601223).

scholarly journals Ampicillin-Ceftriaxone vs Ampicillin-Gentamicin for Definitive Therapy of Enterococcus faecalis Infective Endocarditis: A Propensity Score–Matched, Retrospective Cohort Analysis

2021 ◽  
Vol 8 (4) ◽  
Author(s):  
Niyati H Shah ◽  
Kathleen A Shutt ◽  
Yohei Doi
Keyword(s):  
Infective Endocarditis ◽  
Propensity Score ◽  
Adverse Events ◽  
Cohort Analysis ◽  
Hospital Readmissions ◽  
Length Of Hospital Stay ◽  
The United States ◽  
Aminoglycoside Resistance ◽  
Definitive Therapy ◽  
Significant Difference

Abstract Background Ampicillin-ceftriaxone (AC) has emerged as an alternative antibiotic regimen for enterococcal infective endocarditis (EIE) with reduced toxicity compared with ampicillin-gentamicin (AG), but evidence regarding its success in reducing EIE-associated death in the United States is limited. Methods We conducted a retrospective, propensity score–matched cohort analysis of EIE patients treated with AC or AG between 2010 and 2017 at 3 hospitals in Pittsburgh, Pennsylvania. We assessed all-cause 90-day mortality as the primary outcome and in-hospital mortality, length of hospital stay, hospital readmissions, adverse events, and relapse of bacteremia as the secondary outcomes. Results A total of 190 patients with EIE (100 treated with AC and 90 with AG) were included. Ninety-day mortality was significantly higher with AC than AG (21% vs 8%; P = .02). After propensity score matching, 56 patients in each group remained for the outcomes analysis. Documented aminoglycoside resistance, presence of annular or aortic abscess, and complete pacemaker removal were the significantly different variables between the 2 matched cohorts. We observed no statistically significant difference in 90-day mortality between the 2 treatment groups (11% vs 7%; P = .55). Adverse events were more common in patients treated with AG (25 vs 39; P = .0091), and more patients in the propensity score–matched AG cohort switched antibiotic regimens than in the AC group (10% vs 49%; P &lt; .0001). Conclusions Patients treated with AC demonstrate no significant differences in mortality, treatment failure, or bacteremia relapse compared with AG in a propensity score–matched EIE cohort.

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