Antibiotics are commonly prescribed. In 2021, there were 211.1 million oral antibiotic prescriptions given by healthcare professionals in the outpatient setting. In other terms, that is an estimated 636 oral antibiotic prescriptions per 1000 individuals. To compare this to previous year’s statistics, in 2020, there were 201.9 million oral antibiotic prescriptions given by healthcare professionals in the outpatient setting, meaning 613 oral antibiotic prescriptions per 1000 individuals. Clearly, this shows that the number of antibiotic prescriptions keeps increasing.

According to the Centers for Disease Control (CDC), about 30 % of antibiotics are prescribed unnecessarily in the outpatient setting (See Figure 1). With that being said, it is crucial to discuss and understand the issue of antimicrobial resistance. Due to increased unnecessary prescribing of antibiotics, antimicrobial resistance is on the rise and it has become a serious matter and threat to not just local health, but also global public health. Since the pharmaceutical industry isn’t providing new drugs on the market to make up for the increase in antibiotic resistance, then what has been done to address this growing problem? One answer to that question is antibiotic stewardship programs. 

According to CDC 2021 annual report, the top 5 most common oral antibiotic classes prescribed in the United States were:

Due to antimicrobial resistance, antibiotics lose their effectiveness in fighting off infections. This has led to other implications, such as prolonged hospital stays, increased costs, treatment failures, and much more. On average, patients will be in the hospital for 13 days due to antimicrobial resistance. Therefore, multidrug resistance (MDR) has become a significant challenge in healthcare and has worsened the antimicrobial resistance issue. For example, globally, 500,000 new cases of MDR tuberculosis are diagnosed yearly. On top of everything, it has been shown that the COVID-19 pandemic has set to increase the threat of antimicrobial resistance as well. Overall, pharmaceutical companies have drifted away from this drug development area, which is why there has been a decrease in new antibiotic development for many years.

Antibiotic stewardship programs aim to help this growing problem by improving the use of antibiotics. Physicians and pharmacists have led the majority of antibiotic stewardship programs. These programs ensure that clinicians prescribe antibiotics only when it is necessary, prescribe antibiotics that cover the necessary infection, and do not expose patients to unnecessary antibiotics. To be in accordance with the Centers for Medicare and Medicaid Services, the Joint Commission made it a requirement for hospital settings to have antibiotic stewardship programs implemented. This is a huge win in reducing inappropriate antibiotic use. Antibiotic stewardship programs can be found in various settings, such as hospital settings, outpatient settings, nursing homes, and resource-limited settings. The CDC website has a page with core elements designated to each antibiotic stewardship program setting to understand that each program may differ depending on its location.

Antibiotic resistance has been on the uptrend for quite a while. It is important to know why antibiotics must be carefully prescribed. Antibiotic stewardship programs are one way that this growing problem is being addressed. Hopefully, we will see that antibiotic stewardship efforts have decreased the issue of antibiotic resistance over time.

References:

1. Majumder MAA, Rahman S, Cohall D, et al. Antimicrobial Stewardship: Fighting Antimicrobial Resistance and Protecting Global Public Health. Infect Drug Resist. 2020;13:4713-4738. Published 2020 Dec 29. doi:10.2147/IDR.S290835
2. Barlam TF. The state of antibiotic stewardship programs in 2021: The perspective of an experienced steward. Antimicrob Steward Healthc Epidemiol. 2021;1(1):e20. Published 2021 Aug 5. doi:10.1017/ash.2021.180
3. Measuring outpatient antibiotic prescribing. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/data/outpatient-prescribing/index.html. Published October 5, 2022. Accessed December 1, 2022.
4. Outpatient antibiotic prescriptions — United States, 2021. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/pdfs/Annual-Report-2021-H.pdf. Published October 7, 2021. Accessed December 1, 2022.
5. Outpatient Antibiotic Prescriptions – United States, 2020. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/pdfs/Annual-Report-2020-H.pdf. Published October 7, 2021. Accessed December 1, 2022.
6. Core elements of antibiotic stewardship. Centers for Disease Control and Prevention. https://www.cdc.gov/antibiotic-use/core-elements/index.html. Published April 7, 2021. Accessed December 1, 2022.

There are roughly 30 million adults on a beta blocker in the United States. Beta-blockers have been around for a very long time. This class of medications has both been used for on and off-label purposes. Over the years, their usage has evolved and has been seen in various disease states. Overall, the indications that this class of medications have been utilized in, are heart failure, glaucoma, hypertension, anxiety, migraines, and many others. This beta blocker refresher will provide you with the overview that will potentially spark your interest to dive deeper into each medication discussed.

Most common beta-blockers have been recognized for being either selective beta blockers or non-selective beta-blockers:

Depending on which specific beta-blocker a patient is prescribed, it is important to provide education on that specific drug’s adverse effects. Individuals taking non-selective beta blockers may experience some side effects that are not seen with selective beta blockers due to their mechanism of action. For example, sotalol has a risk for QT prolongation because it blocks potassium channels. The adverse effects are dependent on the specific drug, but there are overall common side effects seen within this class of medications, such as fatigue, hypotension, dizziness, and bradycardia. The less common side effects that individuals should be aware of are insomnia, weight gain,  hepatotoxicity, and bronchospasm. Historically, beta-blockers have been contraindicated in patients with asthma due to their mechanism of action. Also, beta-blockers may mask the signs of hypoglycemia. Patients who have diabetes should be educated on what to do when on a beta blocker just in case they experience hypoglycemia. Beta-blockers, however, have their useful places in therapy. To illustrate, this class of medication has been utilized for its anxiolytic effect. An example is propranolol, which is often prescribed off-label for anxiety or to help with stage performance to reduce some peripheral symptoms associated with anxiety.

Other beta-blocker class pertinent details:

• Individuals should monitor their blood pressure and heart rate while on this medication.
• There are multiple formulations available on the market.
  • The most common routes of administration are oral, intravenous, or ophthalmic.
• The dosage of these medications depends on the specific drug.
  • Some of these medications come in immediate release or extended release.
  • For example, propranolol ranges from 80 mg/day to 320 mg/day, which can be split into multiple doses daily due to its half-life.
• Patients can be on this medication for an extended period of time.

Overall, this class of medication has been on the market for a long time; it is well-established compared to other classes of medications in terms of indications and side effect profiles. It is important to differentiate between selective and non-selective beta-blocker medications to understand their mechanism of action and their respective indications. A large patient population utilizes this class of medications, so it is extra important to keep up with new findings and updates. Hopefully, this refresher on beta-blockers has helped to provide you with beneficial information to continue delivering the best care in your own pharmacy setting.

Dagmara Zajac

RxPharmacist Team

References:

1. Beta-blockers: Types, uses and side effects. Cleveland Clinic. https://my.clevelandclinic.org/health/treatments/22318-beta-blockers. Accessed November 28, 2022.
2. What you should know about beta blockers. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/high-blood-pressure/in-depth/beta-blockers/art-20044522. Published August 13, 2021. Accessed November 28, 2022.
3. Oliver E, Mayor F Jr, D’Ocon P. Beta-blockers: Historical Perspective and Mechanisms of Action. Rev Esp Cardiol (Engl Ed). 2019;72(10):853-862. doi:10.1016/j.rec.2019.04.006
4. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Beta Adrenergic Blocking Agents. [Updated 2018 Jun 3]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548127/
5. Farzam K, Jan A. Beta Blockers. [Updated 2022 Jul 21]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532906/
6. Srinivasan AV. Propranolol: A 50-Year Historical Perspective. Ann Indian Acad Neurol. 2019;22(1):21-26. doi:10.4103/aian.AIAN_201_18

An ample drug supply is important to ensure that patients receive the medications they need. What happens if the drugs patients need are not able to be supplied for reasons that are out of our control? Drug shortages are more common than individuals think. Since 2018, there have been more than 200 ongoing drug shortages on average yearly. Pharmacists can truly help make drug shortages less of an identifiable problem. Everything that pharmacy school teaches pharmacists and pharmacy students is crucial in utilizing and strategizing the temporary or long-term solutions for these drug shortages. The figure below from the American Society of Health System Pharmacists (ASHP) website shows just how many new drug shortages are identified yearly.

Reasons for Current Drug Shortages

Drug shortages can occur for various reasons. Some of those reasons are due to manufacturing issues, the increase in demand for the product, regulatory issues, voluntary or involuntary recalls, shortage of raw materials, and economic issues. Historically, pharmacies sometimes would start to compound a product, but that is only if a product has such a solution for its shortage. For example, some chain hospitals can borrow between their sites to help relieve some of their shortages because depending on a patient population or patient volume for a given hospital, they can have a higher demand for one product over another and have the luxury to loan products between their sites.

Drug Shortages in the Workplace

Depending on certain workplaces, there can be protocols in place for what to do in case a drug becomes unavailable. Sometimes the shortage can be solved temporarily by using an alternative product, but the problem starts when there is no alternative for a given product.  For example, in an inpatient pharmacy setting in a large hospital, there can be weekly meetings in place for staff from different areas of the hospital at various administration levels to discuss drug shortages. During these drug shortage situations, it is important to have transparency between staff members. Clear communication helps create a collaborative environment which can help identify more solutions to situations. Each individual drug in shortage may need its individualized solution. Those solutions depend on the product in shortage, the facility that utilizes that product, the reason for the shortage, the return to market date, and many other factors.

Resources for Drug Shortages:

• ASHP has a whole section on its website dedicated to the drug shortage topic. It is very helpful to utilize it to stay up to date on new drug shortages. Depending on the product, it can list the reason for the shortage, and the estimated resupply dates as well. Also, ASHP has a section on the drug shortage trends that have been seen over the years. ASHP has a section on the website for resolved drug shortage items, which perhaps can be helpful to gain historical knowledge about a given product or its history with shortages.
• The Food and Drug Administration (FDA) has a whole section of its website dedicated to drug shortages. The FDA has a whole database that details breakdowns for each product on shortage in detail by the manufacturer name, shortage duration, specific NDC numbers, and anything else that might be relevant to that given product. The FDA created an app for quicker access and information regarding drug shortages as well.

Drug shortages are clearly complex and not as simple as some may think. They can be caused by various reasons. The solutions for them sometimes can be easy because there is an alternative on the market, but sometimes require a team to figure out temporary strategies and protocols such as compounding the product in pharmacies. It is important for pharmacists everywhere to have these discussions and continually educate other healthcare professionals to prepare for current and future drug shortages. Overall, drug shortages require our immediate attention and responding to the call will ensure that our patients have fewer disruptions to their treatments.

Dagmara Zajac

RxPharmacist Team

References:

1. Center for Drug Evaluation and Research. Drug shortages. U.S. Food and Drug Administration. https://www.fda.gov/drugs/drug-safety-and-availability/drug-shortages. Accessed November 23, 2022.
2. Drug Shortages Statistics. ASHP. https://www.ashp.org/drug-shortages/shortage-resources/drug-shortages-statistics?loginreturnUrl=SSOCheckOnly. Accessed November 23, 2022.
3. Drug Shortages. ASHP. https://www.ashp.org/drug-shortages?loginreturnUrl=SSOCheckOnly. Accessed November 23, 2022.
4. Ventola CL. The drug shortage crisis in the United States: causes, impact, and management strategies. P T. 2011;36(11):740-757.

Background

Multiple medications have been discovered to target cell surface receptors. These are programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). These receptors are specifically selected because they are important targets for cancer therapy. There are some similarities between these receptors, but there are differences to note. For example, the PD-1 receptor is expressed on T cells, B cells, monocytes, dendritic cells, natural killer T cells, and regulatory T cells. On the other hand, PD-L1 is expressed on T cells, B cells, dendritic cells, macrophages, bone marrow-derived mast cells, and a few non-immune cells.  

T-cell exhaustion is commonly characterized by the presence of PD-1. PD-1 expression is found in cancers such as tumor infiltrating lymphocytes. PD-L1 is commonly overexpressed in many different types of tumors, such as tumor-associated macrophages.

To understand how PD-1 and PD-L1 work in the human body, it is best to look at each medication’s mechanism of action. The similarities between PD-1 and (PD-L1) medications are that they are monoclonal antibodies, (MAB) and are all available in an injection dosage form. The doses utilized are specific to the indication that the medication is being used for. Here, we will go into specifics to provide an overview of these medications that target cancer cells.

Medications

Nivolumab is a human IgG4 MAB and was approved by the FDA in 2014. This medication binds to the PD-1 and stops the PD-L1 and programmed death ligand-2 (PD-L2) from interacting with each other, which ultimately allows the PD-1 pathway inhibition to occur. Nivolumab is commonly indicated for:

Nivolumab’s dose strengths are 40 mg/4 mL, 100 mg/10 mL, 120 mg/12 mL, and 240 mg/24 mL solution in a single-dose vial. The common dosages of this medication are 240 mg every two weeks and 480 mg every four weeks. It is important to be aware of the immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic HSCT, and embryo-fetal toxicity associated with this medication. Multiple adverse reactions can occur such as fatigue, rash, musculoskeletal pain, nausea, vomiting, etc. Also, if it is being used with another agent, there are other adverse reactions to consider compared to when it’s being used as a single agent.

Pembrolizumab (approved by the FDA in 2014) is a human IgG4 kappa that targets the PD-1 receptor which is why it has a similar mechanism of action to nivolumab, as well as a similar adverse reaction profile. Pembrolizumab and nivolumab differ in their indications. Some pembrolizumab indications are:

Typical doses in practice are 200 mg every 3 weeks or 400 mg every 6 weeks. The strengths of this medication offered are also 100 mg/4 mL (25 mg/mL) solution in a single-dose vial. The adverse effects profile is similar to nivolumab.

Atezolizumab was granted FDA approval in 2014 and is phage-derived human IgG1 MAB that blocks PD–L1. This medication works by blocking the interaction between PD-1 and B7.1, but it doesn’t induce antibody-dependent cytotoxicity. Some of its indications are:

Some of the dosage forms available are 840 mg/14 mL (60 mg/mL) and 1200 mg/20 mL (60 mg/mL) solution in a single-dose vial. Routinely, doses of 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks are utilized in practice. It is important to be aware of the immune-mediated adverse reactions, infusion-related reactions, complications of allogeneic HSCT, and embryo-fetal toxicity which is similar to PD-1 precautions. The common adverse effects seen are fatigue, decreased appetite, nausea, and cough.

Avelumab is IgG1 human MAB anti-PD-L1. This medication was FDA approved in 2016, and is indicated for:

This medication does warrant premedication and is used as needed thereafter. The common doses seen utilized are 800 mg every 2 weeks. The adverse effect profile is dependent on the indication that it is used for, but it is similar to what patients on atezolizumab experience. The common dosage form seen is 200 mg/10 mL (20 mg/mL) solution in single-dose vial.

Durvalumab is a human MAB that targets PD-L1 and was given FDA approval in 2017. Some of this medication’s indications are:

Some of the injection dosage forms available are in a 500 mg/10 mL (50 mg/mL) and 120 mg/2.4 mL (50 mg/mL) solution in a single-dose vial. Commonly, patients receive either a weight-based dose that is dependent on their current weight, or a fixed dose of 1,500 mg every four weeks. The common adverse effects that patients experience are cough, fatigue, nausea, pneumonitis, and upper respiratory tract infections.

Overall, when comparing PD-1 and PD-L1 medications, examining their different indications, dosage strengths, and side effect profiles can be useful in determining the right therapy for the right patient. The over-expression of PD-1 and PD-L1 in cancer cells is the reason why these receptors have been targeted in studies to identify new medication options for different cancer types. It is important to continue to stay up to date with the latest developments in literature because new and old medications are continuously being studied to find new indications and breakthrough therapies.

-Dagmara Zajac

RxPharmacist Team

References: