Implementation and Impact of a ß-Lactam Allergy Assessment Protocol in a Veteran Population.

BACKGROUND: Approximately 10% of the US population reports having a ß-lactam allergy, although nearly 90% do not have a true immunoglobulin E (IgE)-mediated reaction. This misconception results in using nonpreferred antibiotics, leading to antimicrobial resistance and treatment failure. To evaluate, clarify, and clear ß-lactam allergies, we implemented a pharmacist-driven ß-lactam allergy assessment (BLAA) protocol and penicillin allergy clinic (PAC). The purpose of this study was to illustrate the BLAA process, including the pharmacist-run PAC, and assess the impact on allergy clearance. METHODS: Clinical pharmacy specialists (CPS) evaluated hospitalized veterans with ß-lactam allergies, using the BLAA protocol. Eligible patients could later be seen in PAC. This was a retrospective observational review of the BLAA protocol to assess recommendations for ß-lactam antibiotic use and PAC outcomes. RESULTS: Between November 2017 and February 2020, 278 patients were evaluated, and 32 were seen in the clinic. The most common allergen was penicillin, and the most reported reaction was a rash (27%) or pruritus and urticaria (18%). Through PAC and the BLAA protocol, 86 patients (31%) were cleared for allergy removal, and 188 (68%) were cleared for alternative ß-lactams. The evaluation revealed that 274 patients (99%) were eligible to receive a ß-lactam antibiotic, and only 4 patients (1%) were recommended for avoidance of all ß-lactams. CONCLUSIONS: These findings highlight the utility of the pharmacist-driven BLAA protocol. We illustrated that most patients with documented ß-lactam allergies were eligible for alternative ß-lactams. The implementation of the BLAA protocol and pharmacist-run PAC facilitated allergy clearance and has the potential to promote alternative ß-lactam use.

Impact of ß-Lactam Allergies on Antimicrobial Selection in an Outpatient Setting.

OBJECTIVE: The primary objective of this study was to determine whether patients prescribed nonpreferred antibiotics received appropriate alternative antibiotics. METHODS: This was a retrospective observational analysis of military veteran patients with a ß-lactam allergy treated in an outpatient clinic or emergency department for an infection during a 5-year span. Antibiotic regimens were first stratified as preferred or nonpreferred based on infection-specific guidelines. The nonpreferred regimens were then evaluated for appropriateness based on allergy history and culture and sensitivity reports. RESULTS: Of 445 fills of antibiotics evaluated, 269 met inclusion criteria, comprising 253 unique infections in 80 patients. Patients received nonpreferred antibiotics for their infection type in 57% of cases. Of the nonpreferred antibiotics, 56% were inappropriate based on guideline-recommended alternatives, allergy history, and culture and sensitivity data. Of the 88 allergies, 97% were historical/self-reported and 48% were cutaneous. In addition, 39% of patients safely received ß-lactam antibiotics after documentation of their allergy. CONCLUSIONS: Patients with documented ß-lactam allergies are at high risk of receiving nonpreferred and inappropriate antibiotics, and many reactions likely do not reflect true allergies. These data emphasize the negative impact of the "ß-lactam allergy" label and the importance of reassessing allergies.

Prolonged low-dose methylprednisolone treatment is highly effective in reducing duration of mechanical ventilation and mortality in patients with ARDS.

An updated meta-analysis incorporating nine randomized trials (n = 816) investigating low-to-moderate dose prolonged glucocorticoid treatment in acute respiratory distress syndrome (ARDS) show moderate-to-high quality evidence that glucocorticoid therapy is safe and reduces (i) time to endotracheal extubation, (ii) duration of hospitalization, and (iii) mortality (number to treat to save one life = 7), and increases the number of days free from (i) mechanical ventilation, (ii) intensive care unit stay, and (iii) hospitalization. Recent guideline suggests administering methylprednisolone in patients with early moderate-to-severe (1 mg/kg/day) and late persistent (2 mg/kg/day) ARDS (conditional recommendation based on moderate quality of evidence).

Polymer conjugate of a microtubule destabilizer inhibits lung metastatic melanoma.

Melanoma is the most aggressive type of skin cancer. It is highly metastatic, migrating through lymph nodes to distant sites of the body, especially to lungs, liver and brain. Systemic chemotherapy remains the mainstay of treatment; however, the development of multidrug resistance (MDR) restricts the efficacy of current chemotherapeutic drugs. We synthesized a series of microtubule destabilizers, substituted methoxybenzoyl-ary-thiazole (SMART) compounds, which inhibited tubulin polymerization and effectively circumvented MDR. Due to poor water solubility of SMART compounds, co-solvent delivery is required for their systemic administration, which is usually associated with hepatotoxicity, nephrotoxicity and hemolysis. To solve this problem and also to increase circulation time, we synthesized a new SMART analogue, SMART-OH, and its polymer-drug conjugate, methoxy-poly (ethylene glycol)-block-poly (2-methyl-2-carboxyl-propylene carbonate-graft-SMART-graft-dodecanol) (abbreviated as P-SMART), with 14.3±2.8% drug payload of SMART-OH. Similar to its parent drug, P-SMART showed significant anticancer activity against melanoma cells in cytotoxicity, colony formation, and cell invasion studies. In addition, P-SMART treatment led to cell cycle arrest at G2/M phase and cell accumulation in sub-G1 phase. We established a model of metastatic melanoma to the lung in C57/BL6 albino mice to determine in vivo efficacy of P-SMART and SMART-OH at the dose of 20mg/kg. P-SMART treatment resulted in significant inhibition of tumor growth and prolonged mouse median survival. In conclusion, P-SMART, a novel polymer-microtubule destabilizer conjugate, has the potential to treat metastatic melanoma.

A phosphotyrosine switch regulates organic cation transporters.

Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation.

The role of vitamin D in cancer prevention.

Vitamin D, also known as cholecalciferol, is the precursor to the active steroid hormone 1, 25-dihydroxyvitamin D3 (calcitriol; 1, 25(OH)2D3). The main physiological role for 1, 25(OH)2D3 is to regulate calcium and inorganic phosphate homeostasis for bone health. More recently, vitamin D has been investigated for its effects in the prevention and treatment of a variety of diseases such as cancer, autoimmune disorders, and cardiovascular disease. Preclinical data strongly support a role for vitamin D in the prevention of cancer through its anti-proliferative, pro-apoptotic, and anti-angiogenic effects on cells. Epidemiologic and clinical studies have shown mixed data on the correlation between serum vitamin D levels and cancer risk. This report seeks to outline results from the most recent preclinical and clinical studies investigating the potential role of vitamin D in cancer prevention.

Polymorphic transporters and platinum pharmacodynamics.

Several solute carriers and ATP-binding cassette transporters have been implicated in the influx or efflux of platinum-based chemotherapeutic agents such as cisplatin, carboplatin, and oxaliplatin. Given that many of these proteins are highly polymorphic, the genetic status of these proteins could be an important contributor to the extensive interindividual pharmacokinetic variability associated with the clinical use of these agents. In this review article, we provide an updated overview of the various transporters that have shown promise in animal models or patient populations in facilitating the movement of platinum-based agents across cell membranes, and how their function is associated with drug disposition or pharmacodynamic effects.