Voxelotor: A Novel Treatment for Sickle Cell Disease.

OBJECTIVE: To review the pharmacological characteristics, clinical evidence, and place in therapy of voxelotor for the treatment of sickle cell disease (SCD). DATA SOURCES: A comprehensive literature search of PubMed (1966 to April 2020) was conducted. Key search terms included GBT440, sickle cell, and voxelotor. Other sources were derived from bibliographies of articles, product labeling, manufacturer's website, and news releases. ClinicalTrials.gov was searched for additional studies. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were reviewed and evaluated. Case reports/series and phase 1 through 3 clinical trials were included. DATA SYNTHESIS: SCD is an inherited disorder associated with significant morbidity and early mortality. Three medications approved for SCD reduce SCD-associated complications but do not selectively ameliorate the underlying disease. Voxelotor is a novel agent that targets the pathophysiology of SCD. A phase 3 trial reported an increase in mean Hb level from baseline for voxelotor compared with placebo (1.1 vs -0.1 g/dL; P < 0.001). Voxelotor is generally well tolerated, with common adverse effects including headache, diarrhea, nausea, and arthralgia. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Voxelotor may be considered for patients with SCD who have continued anemia and hemolysis despite being on maximum tolerated dose of hydroxyurea or in those who are hydroxyurea intolerant. Voxelotor is costly; therefore, both cost and benefit should be weighed before prescribing. CONCLUSION: Voxelotor appears to be safe and effective as monotherapy or in combination with hydroxyurea for patients with SCD who are 12 years of age and older.

Adequacy of empiric gram-negative coverage for septic patients at an academic medical center.

BACKGROUND: Gram-negative organisms (GNOs) have increasing resistance rates to levofloxacin at Virginia Commonwealth University Health System (VCUHS), where levofloxacin is the most common agent added to provide double coverage of gram-negative infections. The goal of this study was to determine the adequacy of empiric gram-negative coverage for septic patients at our institution. METHODS: A retrospective review of patients admitted to VCUHS, from January 1, 2014, to December 31, 2014, with a diagnosis of sepsis, severe sepsis, or septic shock and documented infection, was performed to determine the adequacy of various empiric antibiotic combinations. RESULTS: Of 219 patients who met the inclusion criteria, 56% of patients received monotherapy and 21% of patients received combination therapy (2 antibiotics) covering GNOs. GNOs (84%) were susceptible to piperacillin-tazobactam. When used in combination with cefepime and meropenem, levofloxacin did not increase coverage. However, levofloxacin provided an 8% increase in coverage and gentamicin provided an additional 13% increase in coverage, respectively, when used in combination with piperacillin-tazobactam. CONCLUSIONS: Among septic patients at VCUHS, gentamicin provided increased gram-negative coverage when compared with levofloxacin. Although susceptibility to piperacillin-tazobactam alone was relatively low, the combination of piperacillin-tazobactam and gentamicin provided nearly equivalent coverage to meropenem and gentamicin.

Vedolizumab: an α4ß7 integrin antagonist for ulcerative colitis and Crohn's disease.

Ulcerative colitis (UC) and Crohn's disease (CD) are chronic, relapsing inflammatory bowel diseases associated with significant morbidity. Conventional therapies for these diseases include corticosteroids, aminosalicylates, immunomodulators, and monoclonal antibodies. Over the years tumor necrosis factor (TNF)-α antagonists alone or in combination with other therapies have emerged as the cornerstone of treatment for induction and maintenance of remission of moderate to severe UC and CD. Unfortunately, some patients with moderate to severe UC and CD are unable to attain or maintain remission with TNF-α antagonist treatment. Vedolizumab, a humanized monoclonal antibody, is the first integrin receptor antagonist approved that selectively antagonizes α4ß7 gastrointestinal integrin receptors. US Food and Drug Administration approval is for treatment of patients with moderate to severe active UC and CD who have inadequate response with, lost response to, or are intolerant to a TNF-α antagonist or an immunomodulator; or have inadequate response with, are intolerant to, or demonstrate dependence on corticosteroids. When administered according to approved dosing in patients with moderate to severe CD and UC, vedolizumab induces clinical response rates up to 31.4% and 47.1% at week 6, and clinical remission rates up to 39% and 41.8% at week 52, respectively. Serious adverse events reported with vedolizumab include serious infections, malignancies, and anaphylaxis. Since vedolizumab is gastrointestinal selective, to date, it has not shown evidence of causing progressive multifocal leukoencephalopathy; however, postmarketing studies monitoring for this adverse effect are ongoing. Further assessment of vedolizumab earlier in the course of these diseases and in combination with other therapies is warranted.