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.

An Unusual Timing of Amoxicillin-Induced IgA Vasculitis in an Elderly Patient.

Immunoglobulin A vasculitis is a small vessel vasculitis which is usually common in the pediatric group. It is rare in adult population but more severe than in children. Proposed triggers include infections, malignancy and medications. For most part, the association is made when immunoglobulin A vasculitis develops within two weeks after starting the implicated medication. A 66-year-old male who was treated with amoxicillin/clavulanate for presumed right fourth toe infection but returned to the emergency department 48 hours later with palpable purpura of lower limbs, arthralgia with swollen hands and colicky abdominal pain with nausea. Abdominal computed tomography (CT) scan showed mildly dilated small bowel. Skin biopsies showed leukocytoclastic vasculitis with IgA deposit on immunofluorescence. The patient was treated with a short course of steroid and the rash was significantly reduced during subsequent follow-up. Although amoxicillin/clavulanate is widely prescribed, clinicians need to be aware of this risk and immediately stop it if signs of drug-induced vasculitis develop.

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.

Microtubule-associated protein 1 light chain 3 alpha (LC3)-associated phagocytosis is required for the efficient clearance of dead cells.

The recognition and clearance of dead cells is a process that must occur efficiently to prevent an autoimmune or inflammatory response. Recently, a process was identified wherein the autophagy machinery is recruited to pathogen-containing phagosomes, termed MAPLC3A (LC3)-associated phagocytosis (LAP), which results in optimal degradation of the phagocytosed cargo. Here, we describe the engagement of LAP upon uptake of apoptotic, necrotic, and RIPK3-dependent necrotic cells by macrophages. This process is dependent on some members of the classical autophagy pathway, including Beclin1, ATG5, and ATG7. In contrast, ULK1, despite being required for autophagy, is dispensable for LAP induced by uptake of microbes or dead cells. LAP is required for efficient degradation of the engulfed corpse, and in the absence of LAP, engulfment of dead cells results in increased production of proinflammatory cytokines and decreased production of anti-inflammatory cytokines. LAP is triggered by engagement of the TIM4 receptor by either phosphatidylserine (PtdSer)-displaying dead cells or PtdSer-containing liposomes. Therefore, the consequence of phagocytosis of dead cells is strongly affected by those components of the autophagy pathway involved in LAP.

Factors associated with successful matching to dermatology residency programs by reapplicants and other applicants who previously graduated from medical school.

OBJECTIVES: To identify factors associated with and not associated with successful matching and matriculation (hereinafter "matching") to dermatology residency programs for applicants who previously graduated from medical school and to distinguish which factors are within applicants' control. DESIGN: Observational cohort study. SETTING: Six accredited academic dermatology residency training programs in the United States. PARTICIPANTS: A total of 221 residency applicants who previously graduated from medical school and who applied through standardized electronic application to 1 or more of the participating residency training programs. MAIN OUTCOME MEASURE: Matriculation to a dermatology residency program by August 2008 following the 2006 residency application period. RESULTS: Forty-six of 221 former medical school graduates included in this study matched to a dermatology residency program. Factors strongly associated with matching included United States Medical Licensing Examination Step 3 score; submission of letters written by dermatologists from institutions that train dermatology residents; completion of preliminary medicine internships rather than transitional or other internship types; listing of research experience; publishing of medical manuscripts; and completion of non-Accreditation Council for Graduate Medical Examination dermatology fellowships. Factors not associated with increased matching included volunteer work; PhD status; sex; number of posters or presentations at dermatology conferences; quality of journal publications; and first authorship. Most successful applicants limited personal statements to 1 page and did not mention previously failing to match. The study sample represented at least 86% of such nontraditional applicants who matched in 2006. CONCLUSIONS: For candidates seeking to match into dermatology residency programs after graduating from medical school, there are factors within their control that are associated with higher rates of match success. This study provides evidence to assist mentors who counsel such candidates.

Rates of skin cancer screening and prevention counseling by US medical residents.

OBJECTIVE: To determine factors related to residents' self-reported skill level for the skin cancer examination (SCE). DESIGN: Survey of residents in November 2003. SETTING: Four US residency programs. PARTICIPANTS: Medical residents in family medicine, pediatrics, obstetrics and gynecology, and internal medicine and specialists. MAIN OUTCOME MEASURE: Proportion of residents reporting their current skill level for the performance of the SCE. RESULTS: Of 454 surveys distributed, 342 residents completed the survey (75.3% response rate). Clinical training for the SCE during residency was infrequent. During residency, 75.8% were never trained in the SCE, 55.3% never observed an SCE, and 57.4% never practiced the examination. Only 15.9% of residents reported being skilled in the SCE. However, the conduct of 4 SCEs (or slightly more than 1 per each year of residency) was associated with manifold increases in self-reported skill levels. CONCLUSIONS: Information now collected from 7 medical schools and 4 residency programs underscores the need for more supervised opportunities to enable physicians in training to perform an SCE during routine patient examinations.