Trimethoprim/Sulfamethoxazole vs Minocycline for the Treatment of Nonurinary Monomicrobial Stenotrophomonas maltophilia Infections in Hospitalized Patients.

BACKGROUND: Stenotrophomonas maltophilia is an opportunistic, gram-negative bacillus with few therapeutic options due to a high level of intrinsic resistance. Trimethoprim/sulfamethoxazole (SXT) is recommended as the first-line treatment; however, minocycline (MIN) has been shown to have similar clinical outcomes in treating S. maltophilia and addresses concern for increasing resistance to SXT. OBJECTIVE: The objective of this study is to evaluate the efficacy and safety outcomes of nonurinary, monomicrobial infections due to S. maltophilia in hospitalized patients treated with MIN or SXT. METHODS: This was a retrospective study of hospitalized adult patients receiving MIN or SXT for nonurinary monomicrobial S. maltophilia infection from April 1, 2018 to March 31, 2020. The primary outcome was clinical disposition classified as rates of clinical failure, clinical improvement, or clinical success. RESULTS: Eighty-two patients (88.2%) received MIN and 11 patients (11.8%) received SXT initially. Clinical failure occurred in 16 (19.5%) patients in the MIN group and in 4 (36.4%) patients in the SXT group (P = 0.242). Clinical improvement occurred in 11 (13.4%) patients in the MIN group and in 1 (9.1%) patient in the SXT group (P = 1.0). Clinical success occurred in 55 (67.1%) patients in the MIN group and in 6 (54.5%) patients in the SXT group (P = 0.503). Total duration of antimicrobial therapy (P = 0.3198), in-hospital mortality (P = 1.0), hospital length of stay (P = 0.9668), intensive care unit (ICU) length of stay (P = 0.1384), and 30-day readmission (P = 0.686) were similar between groups. CONCLUSIONS AND RELEVANCE: Rates of clinical failure, clinical improvement, or clinical success were similar between MIN and SXT for nonurinary monomicrobial S. maltophilia infections.

A Multicenter Retrospective Evaluation of Direct Oral Anticoagulants for the Treatment of Heparin-Induced Thrombocytopenia.

INTRODUCTION: Direct oral anticoagulants (DOACs) represent an off-label but potential alternative to traditional therapies for heparin-induced thrombocytopenia (HIT). OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of DOACs in patients with a diagnosis of laboratory-confirmed HIT. METHODS: A multicenter retrospective cohort study of adult patients with HIT treated with apixaban, rivaroxaban, or dabigatran between 1 January 2013 and 1 January 2020 was performed. Patients with an intermediate or high pre-test probability for HIT and a positive antiplatelet factor 4/heparin complex assay, latex immunoturbidimetric assay, or serotonin release assay were included for analysis. The primary outcome was the composite of newly diagnosed venous or arterial thromboembolism, gangrene, or severe limb ischemia requiring amputation at 3 months following DOAC initiation. This study was approved by local institutional review boards, and the requirement for informed consent was waived. RESULTS: A total of 77 patients from four health systems were included. The median 4Ts score was 5 (interquartile range 4.5-6), and 38 patients (49.4%) had a diagnosis of HIT with thrombosis. The most frequently used DOAC was apixaban (n = 51), followed by rivaroxaban (n = 24) and dabigatran (n = 2). In total, 63 (81.8%) patients received parenteral non-heparin anticoagulation prior to DOAC initiation. Nine patients (11.7%) experienced the primary outcome of HIT-related thrombotic events. Of the 14 patients who exclusively received DOAC therapy, none experienced the primary outcome. Major bleeding occurred in five (6.5%) patients. CONCLUSION: In this retrospective cohort study, DOACs were associated with rates of thrombotic and hemorrhagic events similar to those with other therapies currently used in the treatment of HIT.

Treatment of Severe Hypertriglyceridemia With Insulin Infusions in Severe COVID-19: A Case Series.

PURPOSE: Rapid onset of severe hypertriglyceridemia was quickly recognized in critical COVID-19 patients. Associated causes have been due to secondary hemophagocytic lymphohystiocytosis (HLH) syndrome, medication-induced, or acute liver failure. Statins, omega-3 polyunsaturated acids, niacin, and fibrates are common oral lipid lowering therapy options in patients at risk for hypertriglyceridemia. The severity of hypertriglyceridemia in COVID-19 patients with triglyceride values reaching greater than 1,000 mg/dL put them at a heightened risk of pancreatitis and therefore an essential need to acutely lower their levels. We present a case series of 5 patients who achieved rapid triglyceride lowering through continuous insulin infusion therapy. METHODS: A retrospective chart review of 48 critical COVID-19 patients who were admitted from March 22 to April 15, 2020 was conducted. Inclusion criteria consisted of mechanical ventilation and continuous insulin infusion to treat severe hypertriglyceridemia resulting with 5 eligible patients in this case report. RESULTS AND CONCLUSION: In addition to standard oral lipid lowering therapies, continuous insulin infusion successfully treated severe hypertriglyceridemia in critically ill COVID-19 patients. None of the patients experienced pancreatitis or hypoglycemia necessitating cessation of insulin. Further studies are needed to show the optimum dose and duration of insulin infusion as monotherapy and in combination with oral therapies.

Sp1/Sp3-dependent regulation of human telomerase reverse transcriptase promoter activity by the bioactive sphingolipid ceramide.

In this study, the roles of Sp1/Sp3 transcription factors in the regulation of the activity of human telomerase reverse transcriptase (hTERT) promoter in response to ceramide were examined in the A549 human lung adenocarcinoma cells. The activity of the N-terminal truncated hTERT promoter, lacking the c-Myc recognition (E-box) region but containing multiple Sp1/Sp3 sites, was also significantly inhibited by C6-ceramide, indicating a role for ceramide in the regulation of Sp1/Sp3 function. Partial inhibition of Sp1 expression using small interfering RNA resulted in a significant inhibition of the hTERT promoter. Treatment with C6-ceramide inhibited the trans-activation function of overexpressed Sp1, whereas it induced the repressor effects of exogenous Sp3 on the hTERT promoter. The interaction between Sp1 and hTERT promoter DNA was significantly reduced in response to ceramide as assessed by chromatin immunoprecipitation analysis. In contrast, the promoter DNA-binding activity of Sp3 was slightly increased in response to C6-ceramide, resulting in the increased ratio of Sp3/Sp1 on the hTERT promoter, which was concomitant with the reduced recruitment of RNA polymerase II to the promoter. Furthermore, mutations of various Sp1/Sp3 recognition sequences significantly attenuated the activity of the promoter in the presence or absence of ceramide, demonstrating the importance of multiple Sp1/Sp3 recognition sites for the promoter activity. Mechanistically, the data demonstrated that C6-ceramide reduced the acetylation of Sp3 protein and partially blocked the activation of the hTERT promoter by the histone deacetylase inhibitor trichostatin A. The roles of endogenous long chain ceramide generated in response to gemcitabine in the inhibition of hTERT promoter activity and the regulation of Sp3 acetylation were also demonstrated.