Exploring Implicit Bias and Its Impact in Pharmacy

After completing this application-based continuing education activity, pharmacists will be able to

· DEFINE different types of bias and how they are formed

· RECOGNIZE what bias may look like in the pharmacy setting

· IDENTIFY how bias can impact patient care

· APPLY methods to address and mitigate bias in the workplace

After completing this application-based continuing education activity, pharmacy technicians will be able to:

· DEFINE different types of bias and how they are formed

· RECOGNIZE what bias may look like in the pharmacy setting

· IDENTIFY how bias can impact patient care

· ILLUSTRATE methods to address and mitigate bias in the workplace

The material presented here does not necessarily reflect the views of The University of Connecticut School of Pharmacy or its co-sponsor affiliates. These materials may discuss uses and dosages for therapeutic products, processes, procedures and inferred diagnoses that have not been approved by the United States Food and Drug Administration. A qualified health care professional should be consulted before using any therapeutic product discussed. All readers and continuing education participants should verify all information and data before treating patients or employing any therapies described in this continuing education activity.

Implicit bias is an important buzzword in healthcare. It has received much attention in the past few years because many researchers have documented its pervasive existence among healthcare providers. Implicit bias involves consciously or unconsciously thinking of some patient groups (or some coworkers) as less important than others, less deserving of care, or simply “less than.” Related concepts include second victim phenomena and imposter syndrome. Good research documents that many people from disenfranchised groups experience implicit or explicit bias when they visit pharmacies. Educational institutions have started to develop programs to educate pharmacists about potential implicit bias before they graduate. Yet most pharmacy personnel who work in clinical contexts have not had such education and need to understand the basic concepts of implicit bias. Pharmacy staff who take time to examine their own attitudes can improve care in influential ways and become significantly more enlightened. This continuing education activity provides basic education on implicit bias and refers readers to evaluation tools.

INTRODUCTION

Can you solve this riddle?

A father and son are involved in a car crash. The son is rushed to the hospital. As the son is about to enter surgery the surgeon says, “I can’t operate—that boy is my son!”

People answer this question in a variety of ways, revealing different implicit biases. Some answers include 1) the boy has two fathers or 2) the father was actually a priest or 3) the whole thing was a dream. Researchers asked this question to two focus groups, one consisting of 197 college students from Boston University and the other, 103 children from Brookline Summer camps.¹ Only 14% of college students and 15% of children answered correctly with the “mom’s the surgeon."¹ A majority of people didn’t guess that the surgeon was the boy’s mother until a few tries, revealing the implicit bias that females are not meant to be doctors or surgeons.

TYPES OF BIAS

Implicit biases are unconscious mental processes that create unintentional automatic associations and reactions.²Implicit bias is more than a stereotype, which is a fixed set of characteristics associated with a particular social group. Implicit bias occurs when people harbor biases unconsciously. A person can develop negative feelings or attitudes towards another person by failing to connect to another person’s identities. The other person may then become part of an “out-group.”²This is not to say that those with shared identities hold no bias towards each other; some women think that women cannot be surgeons, for example. It’s important to look at other factors that cause implicit bias. Besides obvious differences in identities, social norms can influence biases and media outlets, public policy, and even education may magnify bias.² People may not often express implicit biases out loud because of their hidden, unconscious nature. Implicit biases contribute to a person’s explicit biases.

Explicit biases include peoples’ conscious preferences, beliefs, and attitudes, and people may communicate them outright.²For example, people may express explicit biases verbally and expose their prejudicial opinions. Prejudice—a biased response towards a social group and its members based on preconceptions³—may lead to irrational hostility directed towards an individual or group.

In-Group vs Out-Group

Social psychologists have long known that people define themselves in terms of social groups and often malign or disparage others who don't fit into their social groups. People who are part of the “in-group” feel they belong to that group because of social perceptions. People part of the in-group generally have positive views of each other and perceive that the group is composed of individual people.⁴In direct comparison, in-group members view people in the “out-group” negatively because they do not belong to the in-group. People in the in-group characterize the out-group as a homogeneous collective rather than individuals. Thus, it becomes easy for members of the in-group to label the out-group as “all the same” rather than treat them like individuals.⁴

Simply put, in-vs-out group labeling becomes a case of “us-vs-them" with those in the in-group being “us” and those in the out-group being “them.”⁴This tendency explains why hostility can exist between certain groups based on factors like political parties, race, or sexual orientation. This concept of “othering” people is fundamental to understanding how bias can influence personal opinions. Healthcare workers must be mindful of their opinions to ensure biases do not interfere with patient care.

Differentiating Stereotypes, Microaggressions, and Discrimination

Stereotypes are a fixed set of attributes associated with a particular group.²Stereotypes are often untrue or unfair generalizations about people who may appear or identify a certain way. Stereotypical beliefs can lead to displays of microaggression, discrimination, and harmful judgment. Some common examples of stereotypes include

People who wear glasses are smart
Boys are stronger than girls
People with tattoos are dangerous
Men are better drivers than women

Microaggressions are physical or verbal acts that subtly express stereotypical thoughts. A 2010 study tracked high school students (N = 342) over their four-year progression and found that students had experienced 21 different types of microaggressions at least once.⁵ Some examples of reported microaggressions included⁵

Teachers assuming a Black student was poor or illiterate
Hispanic and Asian students were asked to teach “native words” even if they only spoke English
Students of color being called on to speak on behalf of their race

Discrimination is the result of implicit or explicit biases. It causes unfair treatment of individuals and communities based on general policies, practices, or norms.²

PAUSE AND PONDER: What kinds of implicit bias have you observed in your workplace?

Consider this example: Kate was shopping at the rear of a beauty store when suddenly, someone robbed the cashier located at the front of the store. She rushed home and immediately called her friends Mark and Sylvia to share what she had experienced. Mark asked what the robber looked like. Sylvia says, “I didn’t see him. He was probably Black. They usually are.” This demonstrates a stereotype about Black people. Her comments are the microaggressions in this case. Sylvia’s racial bias is what contributed to this reaction.

BIAS SUBGROUPS

Bias comes in many forms and is not limited to particular set of individuals. It can affect any group. Common biases are based on⁶

Beauty
Educational background
Gender
Race/Ethnicity
Religion
Sexual orientation
Socioeconomic background

Unconscious biases are more difficult to identify given that people rarely verbalize them, but they still play crucial roles in affecting behavior and judgment. Bias is a large umbrella term that can further be broken down into subgroups and sub-definitions. Table 1 lists some common categories of unconscious or implicit bias. The SIDEBAR discusses recency bias, a type of bias that can have significant influence on providers’ and patients’ healthcare decisions.

Table 1. Major Biases Present in Everyday Life⁶

Affinity bias	Unconscious preference for people with whom you share qualities or interests
Ageism	Negative feelings towards others based on their age
Attribution bias	Related to how you infer the reasons that others act as they do and misunderstand motivations; individuals may attribute their own accomplishments to skill, but assign no fault to their failures; they may be less generous in their thinking when examining others’ behaviors
Beauty bias	Belief that attractive people are more successful, competent, and qualified than unattractive people; physical appearance is used to judge competency
Confirmation bias	Searching for information that backs the opinion an individual holds and rejecting information that contradicts that opinion
Conformity bias	Others’ views influence an individual’s views; this concept is related to peer pressure and acceptance seeking

SIDEBAR: RECENCY BIAS^7,8

Recency bias affects cognitive decision-making by favoring recent events over historic events to estimate future events. Recency bias is also defined as the tendency to base thinking on what comes easily to mind based on recent events.

For example, an employer is conducting employee evaluations and greets an employee who consistently meets performance goals and expectations. However, the employer chooses to deny the employee a promotion based on a recent mistake. Despite consistent success, a recent error influenced the employer’s decision.

In healthcare settings, some examples of recency bias include

Rejecting older evidence that disproves new (mis)information
Emphasizing recent information and failing to consider the entire evidence set
Seeking new information rather than older, more voluminous, and more consistent facts

ETIOLOGY OF BIAS

Science offers some explanation as to how and why biases form in the human mind. The amygdala and the prefrontal cortex (PFC) are most involved in forming bias.⁹The amygdala, a small structure located in the temporal lobe of the brain, is responsible for receiving direct information from all the body’s sensory organs.³It is the part of the brain that generates responses to stimuli, whether that be arousal, attention, or fear.³The amygdala controls the body’s fight-or-flight response, which is activated in situations that are frightening like walking down a dark alleyway, hearing unfamiliar sounds, or seeing unfamiliar people.^3,10

Several neuroimaging studies have shown that activity in the amygdala heightens when people view pictures that trigger biases. For instance, when people see facial images of those from a different ethnic background than that of their own, the amygdala is activated more so than seeing people who look similar to them.^3,10

The PFC processes cues and is involved with contingency-based learning, decision-making, and evaluation.³Essentially, the PFC communicates with the amygdala to signal that visual or auditory cues may not be a danger at all; it effectively regulates or “calms” immediate amygdala activation based on situational surroundings.^9,10The PFC functions to help the brain adjust to fit the environment’s social norms.

Influences of Bias

Social attitudes and expectations that reinforce stereotypes and microaggressions change the way the brain processes behavior. That said, implicit bias is not intrinsic (or hard-wired), meaning although it may exist in the unconscious parts of the brain, it can be “un-wired.”¹⁰Experiments involving children who had diverse friend groups show less reactive amygdala activation, meaning their brains did not automatically associate negative reactions based on skin color.⁹

What does this have to do with bias? It suggests that bias is not inherently present in children from birth and develops in adolescence.⁹ The social, physical, and economic environment in which people are raised affects brain development and ultimately alters individual implicit biases.

Identity, Individuality, and Intersectionality

People use their social identity to compartmentalize themselves into specific groups or categories. In 1974, sociologist Henri Tajfel first proposed the social identity theory that suggested social identity derives from the “knowledge of membership” in a group (or groups), and that membership in those groups creates individual significance and value.¹¹Social identity defines how individuals characterize their own traits. Common identities include things like¹²

Disability
Ethnicity
Gender or sex
Nationality
Political party
Race
Religion
Economic status

Personal identities are adjectives used to describe oneself, like smart, tall, or funny.¹²

Social identity is dynamic in that it can develop in various ways.¹⁰ For example, society classifies people born in the early 1980s to mid-1990s as being part of the millennial generation. Although membership requires nothing other than birth at a specific time, others group millennials into a category (their generation) that has over time acquired certain characteristics typical of group members. Individuals can also develop identity through conscious choices, like choosing to go into a healthcare profession or going to school to be a writer.¹⁰People are not usually limited to one identity, but rather possess multiple social identities that work to influence a person’s experiences in life.¹² For example, a White man fits into categorical groups of (1) White person and (2) male sex, yet his life experience may differ depending on if he is born into higher socioeconomic class, identifies as heterosexual, or has a disability.

Society’s cultural norms shape identities.¹³ As attitudes towards cultures (or groups) change over time, societal standards change as well. Certain identities may have more value and importance than others because society emphasizes those differences. Identities may also shift importance based on the context in which a person lives. A White American living in North America might think about national identity only infrequently. However, if that person takes a job in China, national identity might suddenly feel like a significant part of individual identity, because it will likely impact how others see the person and how the person interprets experiences.¹²

Social identity overlaps strongly with intersectionality, or the multifaceted interplay of social identities, systems of power, and oppression of certain groups.¹³As mentioned above, social identities exist in various combinations that make individuals unique. Intersectionality allows us to see how different identities may affect one another, and how that in turn relates back to concepts of bias, discrimination, and stereotypes.¹³

Bias within groups can affect intersectionality. For example, studies show that people of color who also identify as part of a sexuality minority experience internalized stigma related to gender and/or sexual orientation within their racial groups; these people experience what is called intersectional minority stress.¹⁴Individuals experiencing discrimination in both racial and gender or sexuality identities are more vulnerable to poor health outcomes given the increased bias and discrimination they face.¹⁴

A public health researcher from the University of Michigan introduced the “weathering” hypothesis, which suggests that Blacks experience health deterioration as a result of chronic social and economic stressors or political marginalization.¹⁵ Some studies have explored and validated this hypothesis. A recent study found that the COVID-19 mortality rate was 2.1 times higher for Black Americans than that of White Americans.¹⁶ The researchers indicate that weathering from chronic and toxic stress magnified COVID-19’s effects in people of color.People of color are more likely to suffer job loss as a result of the COVID-19 outbreak, which in turn affects health insurance coverage and thus contributes to poorer health outcomes. Regardless, even those who possess employment and health insurance are more likely to receive inferior care due to the implicit biases present in healthcare. This study emphasizes the concept of “weathering” in a way that is relevant in our world today.¹⁶

PAUSE AND PONDER: How might implicit biases in your workplace affect patient care and outcomes?

Bias and social identity are entwined. Social identities stem from a person belonging to a group, whether that be an “in-group” or “out-group.” Figure 1 provides examples of the groups, such as middle class or documented citizens. A person can belong to more than one group. Society tends to label certain groups as more valuable than others, which leads to re-enforcement of certain biases. People tend to conform to societal standards, and placing oneself into these groups creates the foundation for bias, stereotypes, and prejudice to occur. It is still important to recognize that while our personal and social identities place us into groups with shared attributes, we are still unique individuals.

SOURCE: Adapted from James R Vanderwoerd ("Web of Oppression"), and Sylvia Duckworth ("Wheel of Power/Privilege")

Institutional Bias

“Power tends to corrupt, and absolute power corrupts absolutely.”

– Lord Acton, British Historian

All people have unconscious or conscious biases. Ultimately, biases result from social identities’ influence on the brain and our environment. But what happens when a collection of individuals with a shared bias comes together? Biases can become discrimination. While prejudice is the pre-conceived notion about someone based on bias, discrimination is conscious, intentionally disparate treatment.¹⁷

Institutional bias, known also as structural bias, ties many issues that arise from discrimination together. Institutional bias—the established laws, customs and practices that methodically reflect and produce group-based inequities in any society—involves policies and practices that are discriminatory beyond that of the individual level.¹⁸ Even in an ideal situation wherein individuals do not possess a certain bias or prejudice towards a group of people, discrimination may still occur because the institutions in which they are involved may have biased practices in place.¹⁸

Nearly every type of social institution exhibits some form of bias against groups of people. Examples of institutions include¹⁸

Education
Environmental management
Healthcare
Law/Criminal justice
Military
Politics
Politics
Retail and housing market
Workforce

Some people allege that individual and institutional bias may not co-exist, but that belief is a bit contradictory. Since the civil rights movement, individual expression of stereotypes and prejudice against Black people in the United States has declined. However, racial discrimination is still widespread and may be as prevalent as it was before the civil right movement in some areas. In 2007, the legal system incarcerated Black people at a rate four times higher than White people in the U.S.¹⁸ Although other factors may contribute to this disparity, institutional racism is still prevalent regardless of individuals’ attitudes or bias towards Black people.¹⁸

Power and legitimacy also influence institutional biases.¹⁸Groups in power are more likely to control institutional bias since they are most likely to control the institutions and create policy.¹⁸Legitimacy is a word used to describe the perception that a policy that is detrimental to the oppressed group is fair or somehow justified.¹⁸

For example, the housing market enables implicit associations between minorities and the risk they present to the value of the neighborhood in which they live or seek to live. As a result, the perception influences certain housing and lending practices for minority applicants.¹⁹Another example is more nuanced. Adults younger than 21 cannot purchase or drink alcohol in the United States; one may argue that this is a form of bias against this age group. However, given the shared societal attitude that teens and young adults should not drink alcohol due to its potential to cause impairment, few people fight against this bias.¹⁸

While some biases are widely accepted, others are clearly not. For example, some immigrants don’t qualify for high level positions within companies. Members of immigrant groups are more likely to take low-level, undesirable positions. As a result, they tend not to stay at that company for long, increasing turnover and decreasing ambition within their fields.¹⁸A similar predicament is the standardized college admission tests; depending on their exam score, students may not qualify for admission to certain schools, perpetuating the idea that they are not smart enough to be admitted.¹⁸Standardized tests fail to take into account students’ different backgrounds; some students benefit from simply being in a higher socioeconomic status with resources available to ensure success.

IMPLICATIONS OF BIAS

Negative attitudes have the potential to affect decision making and health outcomes across various healthcare settings. In 2021, the three largest motivations for hate crimes in the U.S. were race, sexual orientation, and religion.²⁰Maternal mortality rates in the U.S. by race are disproportionate. Black women die during childbirth nearly three times more often than White or Hispanic women.²¹These discrepancies are due to institutional biases and existing racism toward Black women in healthcare. The Centers for Disease Prevention and Control adds that implicit bias prevents people of color from having fair opportunities for economic, physical, and emotional health.²²As part of the healthcare workforce, pharmacists and pharmacy technicians should be able to identify how implicit biases can adversely impact relationships with patients and customers.

PAUSE AND PONDER: Which interventions described in this CE might help you and your coworkers
have frank discussion about bias and discrimination?

Recent research shows people have self-reported experiences of discrimination in healthcare. These instances frequently occur in the following groups of people²³:

LGBTQ (lesbian, gay, bisexual, transgender, queer)
Low socioeconomic status
Older adults

Overweight or obese
Poor health
Racial/ethnic minorities
Uninsured
Women

Patterns of bias and discrimination towards marginalized groups becomes evident. As a result, these individuals can feel perceived discrimination, which is anticipation of unfair treatment they may receive due to their characteristics.²³These groups are more likely to have high stress and mental health disorders such as anxiety, depression, and substance abuse.²³Table 2 lists examples of studies that highlight implicit biases related to healthcare.

Table 2. Studies that Highlight Implicit Biases Related to Healthcare^24-28

A study (N = 142) of emergency response situations showed that White bystanders were slower to provide help to Black victims than the speed at which White bystanders helped White victims. White participants helped 88% of White victims compared to 58% of Black victims. “Help Time” was ~120 sec for Black victims compared to ~40 sec for White victims.

A review (N = 7070) found Black and Latino patients are less likely to receive medication, especially opioids, to alleviate acute pain in the emergency department than White patients (OR 0.60 [95%-CI], 0.43-0.83).

Asian Americans (N = 521) reported feeling like their doctors do not involve them in shared decision making, do not listen to their concerns, and spend less time with them. They were also less likely to receive counseling on mental health or lifestyle issues compared to White patients (N = 3205) in the survey.

An analysis found doctors perceived Black patients (N = 618) to be less educated, less likable, less intelligent, and nonadherent to medical advice and medication therapy. Physicians were less likely to agree that Black patients vs. White patients are `the kind of person they could be friends with’ (34% of White vs. 27% of Black patients).

A survey (N = 316) showed transgender or gender nonconforming people worry about discrimination when they use pharmacy services; 41.6% reported discrimination associated with such services, and 52.5% reported pharmacists as having very little or no competency in providing gender-affirming care.

Gender-Diverse Care and Ageism

An emerging topic is gender-diverse care. The Human Rights Campaign Foundation and the American Pharmacist Association (APhA) released a joint pharmacy resource guide for gender diverse care. The guide includes key terms, inclusive communication, staff training and other essential points of patient centered care for gender diverse patients.²⁹It is accessible for free at https://www.thehrcfoundation.org/professional-resources/transgender-pharmacy-guide

Nicole Avant, PharmD, BCACP, founder, owner, and consultant at Avant Consulting Group, presented key studies on implicit bias during a session at the 2022 National Community Pharmacy Association Annual Convention. They include³⁰

Black women are more likely to die after being diagnosed with breast cancer.
Patients of color (POC) receive fewer cardiovascular interventions and fewer renal transplants than White patients.
POC who have diabetes are more likely to undergo leg amputation.

Poor provider-based interactions negatively impact the quality of care and the desire to seek medical help. This fosters mistrust of healthcare and healthcare workers, like pharmacists and pharmacy technicians. Poor interactions can significantly delay treatment-seeking, which worsens health complications by creating avoidable increases in emergency healthcare use and increasing health disparities. The SIDEBAR provides an example of poor care.

SIDEBAR: A Health Professional’s Observation³¹

Joanne Whitney is a retired pharmacy professor who has shared her experiences when interacting with healthcare providers.

She went to the emergency room for a urinary tract infection (UTI) and severe pain. She asked for hydromorphone (Dilaudid) since it had helped her before, but a young physician told her that they don’t prescribe opioids to “those who seek them.”
Her pain continued for eight hours. She states, “When older people come in like that, they don’t get the same level of commitment to do something to rectify the situation. It’s like ‘Oh, here’s an old person with pain. Well, that happens a lot to older people.’”
She also told the physician the prescribed antibiotic was incorrect for her UTI, but the provider disregarded her concern despite her pharmacy background.

The prejudice in this case is the notion that older people are unpleasant and difficult to treat. Discrimination occurs when healthcare providers do not manage older adults’ needs appropriately or treat them less favorably than younger patients.

Her experience emphasizes ageism in healthcare settings. More than half a million Americans aged 65 and up encountered ageism during the COVID-19 pandemic.

Ageism can be explicit in some healthcare settings. In 2021, an advocacy group for older adults filed a lawsuit in Idaho over the state’s crisis guidelines for hospitals that were overwhelmed with COVID-19 patients. The protocol stated staff should triage and treat younger patients before older adults because “they have more years left” to live.³²

Other examples of ageism prevalent in healthcare today include

Assuming older patients who talk slowly are cognitively compromised
Rushing patients, not listening to their concerns
Only speaking to the patient’s family member
Ignoring or minimizing pain complaints

Racism in Pharmacies

A 2021 U.S. Qualtrics Survey found that nearly 20% of people perceived racial discrimination in community pharmacy settings.²³Of those people, one-third of them felt they had to be particularly careful about their appearance to receive “good service” and avoid harassment.²³On average, people visit doctors and specialists a handful of times but can visit their community pharmacies up to 35 times a year.The study showed that perceived discrimination significantly affects healthcare. One third of respondents stated they tried to avoid certain pharmacies, and 17% reported switching pharmacies.Switching pharmacies may seem like an adequate temporary solution, but in actuality fragments medical records, increases the likelihood that pharmacists will miss potential drug interactions, and compounds adherence issues.²³

Thus, healthcare providers must be cognizant of their biases and avoid acting on them when interacting with patients in pharmacy settings. Pharmacy workers should strive to be fair and aware of their personal implicit biases. They should also be conscientious and deliberate when interacting with patients. Management must ensure adequate training is in place for pharmacists and technicians to create a welcoming, inclusive atmosphere. If it is not, pharmacy employees should suggest it is needed.

Becoming conscious about implicit biases should begin during the education of future pharmacists. Six PharmD programs surveyed students (N = 357) using the Harvard Race Implication Test.³³The test determines implicit associations by measuring the time it takes a person to connect two concepts, i.e. (Black/White to good/bad). The survey found that pharmacy students exhibited preference for White patients and moderately negative implicit and explicit bias towards Black patients.³³Although many pharmacy schools have already incorporated the concepts of cultural competence, increasing awareness of how implicit biases negatively affect patient interactions should be a focus area.

Bias Affecting Decision-Making Processes 

Implicit bias has been associated with several downstream effects. Consider “second victim” effect. The term “second victim” describes healthcare professionals and the unanticipated emotional impact they feel after making a medical or clinical error.³⁴Medical errors are one of the top leading causes of death in the U.S.³⁵The first victim is the patient who experiences the medical error. The second victim—the person who made the errors—feels distress and personal responsibility after an unexpected adverse patient outcome or error. This directly impacts the healthcare professional’s career and life.³⁴ In many cases, implicit bias is not a factor in second victim effect, but sometimes it is. For example, consider a provider who has an implicit bias towards Black women. The provider fails to intervene aggressively when a patient, a Black woman, is experiencing pain and hemorrhaging due to complications during childbirth. The patient soon becomes unconscious from blood loss. The patient unfortunately dies. The patient’s family files a complaint with the hospital regarding the provider’s lack of standard care during her birthing process. The provider is then afflicted by second-victim effect.

Many second victims suffer from job-related emotional and physical stress, and their additional feelings of powerlessness and insecurity can prompt them to leave the profession.³⁴Lack of support for coworkers and management contributes to the second victim phenomenon, and coworkers and managers may be less likely to support the second victim if they have biases against that person for some reason.³⁴The second victim’s self-blaming negative feelings could influence future decision making.

Nearly half of healthcare professionals experience second victim effect at least once in their careers.³⁴This effect may lead to changes in clinical judgment and inadvertently affect patient care. It is important to recognize when it occurs. To combat second victim phenomenon’s negative effects, mindfulness-based interventions have shown efficacy in reducing stress and burnout.³⁴Also, psychological first aid fosters resilience in healthcare professionals by establishing formal support teams within health institutions.³⁶This includes education about normal responses to traumatic events, active listening skills, understanding the importance of nutrition and rest, and clarifying when to seek help.³⁶

Interprofessional Bias

Interprofessional collaboration is an important part of managing and delivering quality patient care. Biases about other professions can create conflict within the team, which has negative consequences for communication, decision-making, and trust.³⁷Implicit biases influence a person’s actions unconsciously and can intrude in various cultural and structural settings. For example, individuals may have preferences for certain specialties or simply certain people over others. Their implicit biases can influence decisions, like who rounds on an inpatient hospital team.The traditional hierarchy of physicians as team “leaders” can create tension within a group that must work with (as equals), but not for (as subordinates), that physician.³⁷

Research shows that biases adversely affect the quality of healthcare delivered to patients. A systematic review on implicit biases in interprofessional collaboration found that biases between professions were predominately negative.³⁷The review mentioned the concept of internalization, which describes how people internalize biases towards their profession towards their own self and behaviors.³⁷For example, physicians mostly saw themselves as leaders while nurses consistently perceived themselves as powerless and lacking authority. As such, physicians exhibit behaviors such as authoritatively shutting down communication in case conferences, whereas non-physician professionals tended to be silent, less engaged, or chose to skip team meetings. Bias internalization influenced which professions voiced their opinions and inhibited the team’s overall growth.³⁷Consequently, these healthcare teams developed feelings of disrespect and mistrust, which impedes patient care. Another study found that when team members perceived they were not consulted about a decision, they exhibited defensive posturing and frustration in meetings.³⁸

Imposter Syndrome

Imposter syndrome is defined as self-doubt about intellect, skills or accomplishments among high achieving individuals.³⁹Imposter syndrome and disorders such as depression and anxiety are often comorbid.³⁹Many healthcare professionals strive for perfection, but those with imposter syndrome tend to associate their success with random chance as opposed to their own intelligence.³⁹Imposter syndrome tends to be more common in marginalized groups (e.g., minority races) in high pressure settings due to underrepresentation in the field; poor representation and pressure exacerbate imposter syndrome.³⁹ It may also be a result of lifelong bias and discrimination, which can affect professionals in their clinical roles as well.

Interestingly, a study of pharmacy residents (N = 720) found higher Clance Imposter Scale scores correlated with the number of hours worked per week and prior mental health treatment, factors associated with high stakes learning environments.⁴⁰This study validates other studies done with various medical professionals and demonstrates the connection between highly focused academic and healthcare areas and the increased likelihood of imposter syndrome.⁴⁰

Imposter syndrome, like the second victim effect, can affect clinical judgement in healthcare professions. It may promote certain biases when they normally would not be due to those feelings of inadequacy, and thus mistakes occur.

Bias in the Pharmacy

Pharmacists hold crucial positions in healthcare, especially since they engage with diverse groups of patients regardless of the setting in which they work. Pharmacists can stimulate broader efforts to address health disparities, especially as their scope of practice widens.⁴¹Social determinants of health (SDOH) are the social and structural conditions in which people are born, live, and work.⁴²Figure 2 shows the key SDOH.

Source: Healthy People 2030, U.S. Department of Health and Human Services, Office of Disease Prevention and Health Promotion. Retrieved July 28, 2023, from https://health.gov/healthypeople/objectives-and-data/social-determinants-health

A 2016 review of pharmacy literature highlighted issues stemming from SDOH affecting pharmacies. These factors are known to influence health outcomes, and pharmacy workers need to be aware when SDH may affect the population they serve. The study showed the following knowledge gaps among pharmacists⁴¹:

Mental illness
Substance/drug abuse with prescription and illicit drugs
Those at risk for HIV/AIDS or hepatitis C infection

Although pharmacists provide care to groups that suffer from effects of SDH, they may not understand entirely or have access to information that could expose SDH. More education on cultural competency is needed within pharmacy.⁴¹

Bias can influence the pharmacy workforce. Perhaps one of the most relevant examples of bias in pharmacy workers concerns opioid use disorder (OUD). The U.S. has battled the opioid crisis for more than two decades.⁴³Those who suffer with OUD are often stigmatized. Pharmacists and pharmacy technicians frequently interact with patients who are diagnosed with such disorders. The lack of knowledge and understanding surrounding OUD underscores biases that exist towards people with OUD.

A small study that examined pharmacy technicians’ attitudes (N = 46) using focus groups found that participants had negative perceptions of patients using opioids. Pharmacy technicians reported “ever-present” negative feelings (meaning they persisted over time) toward patients with OUD, even if they did not know opioid’s indication for a particular person.⁴³The researchers asked pharmacy technicians to recount their experiences with patients who recieved opioids. Figure 3 highlights their perceptions.⁴³

Figure 3. Comments from Pharmacy Staff about Patients with OUD⁴³

A multitude of reasons may explain why participants felt this way. Their experiences may be tied to aggressive encounters between healthcare professionals and patients who use opioids and negative media portrayals of opioid use.⁴³The study went into further detail on early refills, a situation where patients want to fill a prescription when their fill histories indicate it’s too early. Most technicians stated they tried to be compassionate and non-judgmental in these situations to overcome the stigmas associated with opioid prescriptions.⁴³

The discussion further explained that the negative perception of patients who take opioids compromises quality of care because it is difficult to reverse formed opinions. The National Institute on Drug Abuse stresses the importance of accurate, complete medication histories and reporting to prescription drug monitoring programs to create healthier patient-provider relationships in the pharmacy.⁴³

Another study focused on pharmacy personnel responses to expedited partner therapy (EPT) in the management of sexually transmitted infections. EPT effectively prevents chlamydia and gonorrhea infections for partners of patients already infected.⁴⁴Providers can give patients diagnosed with chlamydia or gonorrhea prescriptions for the partner without having to name the partner. EPT is protected by law in 41 states and supported by numerous organizations including⁴⁴

American Academy of Pediatrics

American Academy of Family Physicians
American Congress of Obstetricians and Gynecologists
Society of Adolescent Health and Medicine

The study (N = 50) found pharmacists refused to fill 58% of EPT prescriptions, and suburban pharmacists were more likely to refuse than city pharmacists.⁴⁴Refusal was more likely if the pharmacists were older than the patient and if patients were White.Pharmacists most commonly cited lack of name on the prescription as the reason for refusal, even if the law does not require a partner name. This indicates a general lack of knowledge about EPT among study participants, which may have contributed to their decisions.⁴⁴

A literature review on weight management programs found implicit and explicit weight bias exists within the pharmacy profession. Weight management programs can vary, and pharmacies offer some in conjunction with prescription medications and nonpharmacologic lifestyle interventions.⁴⁵The review found stigmatizing language in the screening processes for weight management programs. It is unclear to what extent weight biased communication exists between pharmacists to patients.⁴⁵ The stigma that surrounds obesity affects other related health problems, like diabetes or cardiovascular concerns, and can weaken the pharmacist-patient relationship.⁴⁵

ADDRESSING BIAS

Implicit biases are present in all people, but the importance lies not in the existence of bias, but how to overcome it. Several strategies address biases, the most important being education in pharmacy school curriculums. Many studies use the IAT to measure implicit bias. The test is free to the public and can be found here: https://implicit.harvard.edu/implicit/

Learners should note that this is not just one test, but a series of different tests.

The IAT measures the time it takes for the individual to match concepts in categories to descriptive words, like race, skin tone, and weight to good, bad, or other stereotypical language.^46,47An individual’s underlying beliefs drive responses time, thus measuring the strength of the association between concepts (a person, image, etc.) and evaluations (good, bad). Researchers recommend incorporating the IAT in curriculums prior to before direct patient exposure.⁴⁶

Other interventions that may be helpful in pharmacy education and other pharmacy settings include⁴⁴

Practicing mindfulness (directing active, open attention to the present to examine one’s thoughts and feelings without judging them). Mindfulness reduces the likelihood of activating implicit biases and enhances the ability to control biases in patient care situations.
Self-awareness/self-reflection training: After completing the IAT, individuals can reflect on identified biases.

Activating goals: Healthcare workers can identify goals that promote fairness and equality for patients and coworkers.
Stereotype replacement: Individuals who collect information that is opposite of cultural stereotypes can replace stereotypical thoughts with non-biased thoughts.
Case studies observing implicit bias: Analyzing case studies where implicit bias was involved helps people recognize how to approach situations differently.
Individuating: This action challenges people to see others for their individual traits as opposing to grouping them by their stereotypical components.
Perspective-taking: This “walk a mile in their shoes” activity asks individuals to assume the perspective of a stigmatized or marginalized member to build empathy.

The University of Utah Pharmacy Residency program implemented an implicit bias awareness and action seminar with four training modules and a pre- and post-test survey. After training, pharmacy residents indicated higher comfort and confidence addressing personal biases and were better able to identify biases of others.⁴⁷While not accessible to the public, this shows that implementing training programs makes a difference in future of pharmacy delivered care.

Conclusion

Implicit biases have overall negative effects on patient care, which is detrimental to patients and those that harbor the implicit biases. Pharmacists and pharmacy technicians who are aware of and take steps to address their implicit biases will improve the way they treat patients and each other as colleagues.

Exploring Implicit Bias and Its Impact in Pharmacy
POST-TEST Pharmacists
Learning Objectives
After completing the continuing education activity, pharmacists will be able to
• DEFINE different types of bias and how they are formed
• RECOGNIZE what bias may look like in the pharmacy setting
• IDENTIFY how bias can impact patient care
• APPLY methods to address and mitigate bias in the workplace

1. You are a 52-year-old clinical pharmacist who works with an interprofessional team. The doctor is a 33-year-old resident who has just started working at the hospital. He does not ask for your input, yet you have caught several prescribing errors he made. He also ignores your questions. He has openly stated that he thinks pharmacists “don’t know what they are talking about.” What potential bias may be occurring?
a. Age bias
b. Interprofessional bias
c. Confirmation bias

2. Which strategy could potentially help mitigate implicit biases in pharmacy education or clinical settings?
a. Behavioral therapy
b. Anonymous reporting
c. Self-awareness training

3. Which of the following statements best describes an explicit bias?
a. “Women who have children are not serious about professional careers.”
b. “Pharmacists and doctors have more clinical education than nurses do.”
c. “Patients of color receive fewer primary care interventions than White patients.”

4. Which of the following statements is CORRECT regarding the etiology of bias?
a. The amygdala processes cues and “calms” the PFC to adjust to social norms.
b. Neuroimaging studies do not associate amygdala activity and bias.
c. Bias triggers amygdala activity and affects decision-making processes.

5. How does bias negatively impact marginalized pharmacy customers?
a. Patients struggle to fill medications due to shortages.
b. Patients feel they have to be careful of their appearance.
c. There is not really bias towards patients in pharmacy.

6. A new pharmacy resident was paged to attend a stroke code and unfortunately, the patient died because the resident did not know which medication to give at the moment. This was the fifth unsuccessful stroke code this month, and the resident is troubled. He starts drinking more after his work shift to help cope with the feelings of loss. After several months, he is diagnosed with depression. He is often late to work and his supervisors counsel him several times. What is the resident experiencing?
a. The resident is experiencing second victim syndrome.
b. The resident does not like his job or his bosses.
c. The resident is experiencing imposter syndrome.

7. Which choice correctly defines social identity and intersectionality?
a. Social identity is the relationship between intersectionality and systems of power; intersectionality is the process of being placed into a group
b. Social identity and intersectionality are different terms for the same concept, and researcher tend to use the two interchangeably in studies and review articles
c. Social identity relates to being placed in an “out-group” or “in-group”; intersectionality is the relationship between social identities and power systems

8. How does the Implicit Association Test (IAT) work?
a. It measures how fast White responders help Black victims in emergencies.
b. It measures the strength of participants’ personal beliefs towards minorities.
c. It measures how quickly participants associate concepts to categories.

9. Which of the following statements about bias internalization is TRUE?
a. Internalized bias has no impact on teamwork, and affects only the individual.
b. Internalized bias has no impact on individual, and affects only the whole team.
c. A bias toward a group of people can be internalized and applied to one’s self.

10. A recently pharmacy graduated has been hired to work on your team. You notice that the new pharmacist tends to hand off minority patients who need a language interpreter to other coworkers. You bring this up to your supervisor, who asks for your suggestions. Which statement is the best intervention?
a. The supervisor should call a team meeting and directly address the new pharmacist in front of everyone to hold that person accountable.
b. The team should review case studies similar to the minority patients so the new pharmacist can feel more comfortable working on those cases.
c. The manager should fire the new pharmacist because recent graduates should know how to manage all cases, even when an interpreter is needed.

Pharmacy technician post-test

After completing the continuing education activity, the pharmacy technician will be able to:
• define different types of bias and how they are formed
• recognize what bias may look like in the pharmacy setting
• identify how bias can impact patient care
• illustrate understanding of strategies that mitigate bias

1. A female technician has worked in a retail pharmacy for several years. She notices the pharmacist always asks for the male technicians to help her put away the order, despite her being there much longer than they have. When she asks the pharmacist why she doesn’t ask for her help, the pharmacist says, “Oh, I just thought it was too heavy for you.” Which statement best describes this case?
a. Male technicians are better and more efficient workers than female technicians.
b. The pharmacist does not like working with the female technician.
c. The pharmacist’s thinking that females are not as strong as males is gender bias.

2. Which statement correctly identifies the differences between explicit and implicit bias?
a. Implicit biases are unconscious; explicit biases are conscious.
b. Explicit biases are harsher than implicit biases.
c. Implicit biases do not have anything to do with explicit biases.

3. You work in a retail pharmacy and a patient drops off a new prescription for Suboxone. When the patient comes to pick up the medication, you notice he is defensive when you ask to see an ID for verification purposes. What is one possible reason for their reaction?
a. The patient feels you may be judging him for his prescription.
b. The patient is offended and thinks you are calling him old.
c. The patient does not have his ID with him at the moment.

4. A female inpatient pharmacy technician is working with a male pharmacy resident to perform a medication history review. The tech notices the resident tends to rush through the interactions with older patients and will only speak to the family if they are present in the room. The tech has overheard this resident state he thinks the nurses should take medication histories since residents have “more important jobs than nurses.” With regard to the pharmacy resident, which bias may negatively affect patient care the most?
a. Affinity bias
b. Interprofessional bias
c. Age bias

5. Which statement is a microaggression?
a. A doctor says “Black women are at higher risks for maternal mortality.”
b. A faculty member says, “Most Black students are poor or illiterate”
c. A patient says, “I want to speak with to the doctor I saw last month.”

6. An APRN is concerned with a medication dose and asks to speak to the pharmacist. When finished with the call, the pharmacist turns to you and says, “APRNs are so incompetent. They never know how to send things over the right way.” Which statement describes the bias the pharmacist is displaying?
a. The pharmacist shows interprofessional bias towards the APRN.
b. The pharmacist in this example is not showing any explicit bias.
c. The pharmacist shows unprofessional bias towards the APRN.

7. How can practicing mindfulness help reduce biases in healthcare settings?
a. It reduces the likelihood of activating implicit biases and enhances the ability to control biases in patient care.
b. It helps healthcare providers take on the perspective of stigmatized or marginalized group members to build empathy.
c. It is designed to let healthcare providers develop goals that promote fairness and equality among coworkers.

8. Over the course of your career in pharmacy, you come to realize that your initial belief that patients who are prescribed multiple refills of opioids are abusing them is wrong. What is this an example of?
a. Stereotype
b. Interprofessional Bias
c. Ageism

9. Which statement describes how the brain plays a role in forming bias?
a. The amygdala and PFC both process social cues that turn to bias most of the time.
b. The PFC is triggered by sensory information while the amygdala processes cues.
c. The amygdala is triggered by sensory information while the PFC processes cues.

10. Which is an example of how implicit biases can influence institutional bias?
a. A Black male is unable to cast his vote at the ballots because he forgot his ID at home
b. A young Hispanic female is denied pain medication because the doctor thinks she’s exaggerating her pain
c. A disabled male athlete does not qualify for a sporting event because he places last in the competition

References

1. Barlow R. Bu research: A Riddle reveals depth of gender bias: BU Today. Boston University. Published January 16, 2014. Accessed April 10, 2023. https://www.bu.edu/articles/2014/bu-research-riddle-reveals-the-depth-of-gender-bias/
2. Vela MB, Erondu AI, Smith NA, Peek ME, Woodruff JN, Chin MH. Eliminating Explicit and Implicit Biases in Health Care: Evidence and Research Needs. Annu Rev Public Health. 2022;43:477-501. doi:10.1146/annurev-publhealth-052620-103528
3. Amodio DM. The neuroscience of prejudice and stereotyping. Nat Rev Neurosci. 2014;15(10):670-682. doi:10.1038/nrn3800
4. Ashcraft D, Treadwell T. Chapter VII: The Social Psychology of Online Collaborative Learning: The Good, the Bad, and the Awkward. In Orvis K, Lassiter A, eds. Computer-Supported Collaborative Learning: Best Practices and Principles for Instructors. IGI Global; 2008:11-15. doi.org/10.4018/978-1-59904-753-9.ch007
5. Sparks SD. Fighting Subtle Bias: Classroom Biases Hinder Students’ Learning. Published October 27, 2015; Accessed April 10, 2023. https://www.edweek.org/leadership/classroom-biases-hinder-students-learning/2015/10
6. Murphy N. Types of Bias. CPD Online College. Published November 10, 2021. Updated May 27, 2022. Accessed April 10, 2023. https://cpdonline.co.uk/knowledge-base/safeguarding/types-of-bias/
7. Phillips-Wren G, Power DJ, Mora M. Cognitive bias, decision styles, and risk attitudes in decision making and DSS. J Decision Syst. 2019;28(2):63-66. doi: 10.1080/12460125.2019.1646509
8. Salim A, Johnson WE. How Bias and Perception Impact Complicance.https://assets.hcca-info.org/Portals/0/PDFs/Resources/Conference_Handouts/Compliance_Institute/2019/304_Bias%20and%20Perception.pdf
9. Weichselbaum C, Banks K. Racism on the Brain. Fron Young Minds. 2021;9:1-8. doi:10.3389/frym.2021.608843
10. Agarwal P. What Neuroimaging Can Tell Us about Our Unconscious Biases. Published April 12, 2020. Accessed April 12, 2023 https://blogs.scientificamerican.com/observations/what-neuroimaging-can-tell-us-about-our-unconscious-biases/
11. Everett JAC, Faber NS, Crockett M. Preferences and beliefs in ingroup favoritism. Fron Behav Neurosci. 2015;9:1-21. doi:10.3389/fnbeh.2015.00015
12. Leading Effectively Staff. Understand Social Identity to Lead in a Changing World. Published February 7, 2023. Accessed April 10, 2023. https://www.ccl.org/articles/leading-effectively-articles/understand-social-identity-to-lead-in-a-changing-world/
13. Kearney, DB. Universal Design for Learning (UDL) for Inclusion, Diversity, Equity, and Accessibility (IDEA). Module 4.2 Positionality and Intersectionality. eCampus Ontario; 2022. Accessed April 10, 2023. https://ecampusontario.pressbooks.pub/universaldesign/
14. Sarno EL, Swann G, Newcomb ME, Whitton SW. Intersectional minority stress and identity conflict among sexual and gender minority people of color assigned female at birth. Cultur Divers Ethnic Minor Psychol. 2021;27(3):408-417. doi:10.1037/cdp0000412
15. Geronimus AT, Hicken M, Keene D, Bound J. "Weathering" and age patterns of allostatic load scores among blacks and whites in the United States. Am J Public Health. 2006;96(5):826-833. doi:10.2105/AJPH.2004.060749
16. Johnson-Agbakwu, C.E., Ali, N.S., Oxford, C.M. et al. Racism, COVID-19, and Health Inequity in the USA: a Call to Action. J. Racial Ethn Health Disparities. 2022;9: 52–58.
17. López L, Betancourt JR. Racial and Ethnic Disparities in Health Care. In: Loscalzo J, Fauci A, Kasper D, Hauser S, Longo D, Jameson J. eds. Harrison's Principles of Internal Medicine, 21e. McGraw Hill; 2022. Accessed April 10, 2023. https://accesspharmacy.mhmedical.com/content.aspx?bookid=3095§ionid=263343935
18. Henry, P. Institutional Bias. In: Dovidio JF, Hewstone M, Glick P, Esses VM, eds. Handbook of Prejudice, Stereotyping, and Discrimination. Sage; 2010:426-440
19. Olinger J, Capatosto K, McKay MA, et al. Challenging Race as Risk: How Implicit Bias Undermines Housing Opportunity in America. Ohio State University; 2017:1-85. Accessed July 20, 2023. https://kirwaninstitute.osu.edu/research/challenging-race-risk-implicit-bias-housing
20. FBI. Number of Victims of Hate Crime in The United States in 2021, by Motivation. Statista. Published March 13, 2023, Accessed April 10, 2023. https://www.statista.com/statistics/737648/number-of-hate-crime-victims-in-the-us-by-motivation/
21. Hoyert DL. Maternal mortality rates in the United States, 2020. NCHS Health E-Stats. 2022. doi.org/10.15620/cdc:113967
22. Working Together to Reduce Black Maternal Mortality. CDC. Updated April 3, 2023. Accessed April 10, 2023. https://www.cdc.gov/healthequity/features/maternal-mortality/index.htm
23. Baffoe JO, Moczygemba LR, Brown CM. Perceived discrimination in the community pharmacy: A cross-sectional, national survey of adults. J Am Pharm Assoc. 2022;63(2):518-528. doi:10.1016/j.japh.2022.10.016
24. Kunstman JW, Plant EA. Racing to help: Racial bias in high emergency helping situations. J Pers Socl Psych. 2008;95(6)1499-1510. doi.org/10.1037/a0012822
25. Lee P, Le Saux M, Siegel R, et al. Racial and ethnic disparities in the management of acute pain in US emergency departments: Meta-analysis and systematic review. Am J Emerg Med. 2019;37(9):1770-1777. doi:10.1016/j.ajem.2019.06.014
26. Ngo-Metzger Q, Legedza AT, Phillips RS. Asian Americans' reports of their health care experiences. Results of a national survey. J Gen Intern Med. 2004;19(2):111-119. doi:10.1111/j.1525-1497.2004.30143.x
27. van Ryn M, Burke J. The effect of patient race and socio-economic status on physicians' perceptions of patients. Soc Sci Med. 2000;50(6):813-828. doi:10.1016/s0277-9536(99)00338-x
28. Lewis NJW, Batra P, Misiolek BA, Rockafellow S, Tupper C. Transgender/gender nonconforming adults' worries and coping actions related to discrimination: Relevance to pharmacist care. Am J Health Syst Pharm. 2019;76(8):512-520. doi:10.1093/ajhp/zxz023
29. Human Rights Campaign Foundation, APhA. Providing Inclusive Care and Services for the Transgender and Gender Diverse Community: A Pharmacy Resource Guide. Published March 2021. Accessed April 10, 2023. https://www.thehrcfoundation.org/professional-resources/transgender-pharmacy-guide#overview
30. Hippensteele A. Expert: 'we all hold implicit biases' that may contradict explicit beliefs, impact patient health. Pharmacy Times. Published October 2, 2022. Accessed April 10, 2023. https://www.pharmacytimes.com/view/expert-we-all-hold-implicit-biases-that-may-contradict-explicit-beliefs-impact-patient-health
31. Graham J. 'they treat me like I'm old and stupid': Seniors decry health providers' age bias. KFF Health News. Published October 20, 2021. Accessed April 10, 2023. https://kffhealthnews.org/news/article/ageism-health-care-seniors-decry-bias-inappropriate-treatment/
32. Boone R. Civil rights complaint targets Idaho Health Care Rationing. AP News. Published September 24, 2021. Accessed April 10, 2023. https://apnews.com/article/coronavirus-pandemic-business-discrimination-race-and-ethnicity-idaho-4a152d4f4f809bfb6588b9025c400d6b
33. Santee J, Barnes K, Borja-Hart N, et al. Correlation Between Pharmacy Students' Implicit Bias Scores, Explicit Bias Scores, and Responses to Clinical Cases. Am J Pharm Educ. 2022;86(1):8587. doi:10.5688/ajpe858
34. Miller CS, Scott SD, Beck M. Second victims and mindfulness: A systematic review. J Pat Saf Risk Manag. 2019;24(3):108-117. doi:10.1177/2516043519838176
35. Coughlan B, Powell D, Higgins MF. The Second Victim: a Review. Eur J Obstet Gynecol Reprod Biol. 2017;213:11-16. doi:10.1016/j.ejogrb.2017.04.002
36. Everly GS. Psychological first aid to support healthcare professionals. J Pat Saf Risk Manag. 2020;25(4):159-162. doi:10.1177/2516043520944637
37. Sukhera J, Bertram K, Hendrikx S, et al. Exploring implicit influences on interprofessional collaboration: a scoping review. J Interprof Care. 2022;36(5):716-724. doi:10.1080/13561820.2021.1979946
38. Simpson A. The impact of team processes on psychiatric case management. J Adv Nurs. 2007;60(4):409-418 doi:10.1111/j.1365-2648.2007.04402.x
39. Huecker MR, Shreffler J, McKeny PT, Davis D. Imposter Phenomenon. In: StatPearls. Treasure Island (FL): StatPearls Publishing; September 9, 2022.
40. Sullivan JB, Ryba NL. Prevalence of impostor phenomenon and assessment of well-being in pharmacy residents. Am J Health Syst Pharm. 2020;77(9):690-696. doi:10.1093/ajhp/zxaa041
41. Wenger LM, Rosenthal M, Sharpe JP, Waite N. Confronting inequities: A scoping review of the literature on pharmacist practice and health-related disparities. Res Social Adm Pharm. 2016;12(2):175-217. doi:10.1016/j.sapharm.2015.05.011
42. CDC. Social Determinants of Health. Centers for Disease Control and Prevention. Published 2022. https://www.cdc.gov/about/sdoh/index.html
43. Cernasev A, Desselle S, Hohmeier KC, Canedo J, Tran B, Wheeler J. Pharmacy Technicians, Stigma, and Compassion Fatigue: Front-Line Perspectives of Pharmacy and the US Opioid Epidemic. Int J Envir Res Pub Health. 2021; 18(12):6231. doi:10.3390/ijerph18126231
44. Borchardt LN, Pickett ML, Tan KT, Visotcky AM, Drendel AL. Expedited Partner Therapy: Pharmacist Refusal of Legal Prescriptions. Sex Transm Dis. 2018;45(5):350-353. doi:10.1097/OLQ.0000000000000751
45. Murphy AL, Gardner DM. A scoping review of weight bias by community pharmacists towards people with obesity and mental illness. Can Pharm J (Ott). 2016;149(4):226-235. doi:10.1177/1715163516651242
46. Prasad-Reddy L, Fina P, Kerner D, Daisy-Bell B. The Impact of Implicit Biases in Pharmacy Education. Am J Pharm Educ. 2022;86(1):8518. doi:10.5688/ajpe8518
47. Terry K, Nickman NA, Mullin S, Ghule P, Tyler LS. Implementation of implicit bias awareness and action training in a pharmacy residency program. Am J Health Syst Pharm. 2022;79(21):1929-1937. doi:10.1093/ajhp/zxac199

All “Prior Authorizations” are Not Created Equal: A Guide to Medicare Part D Prescription Drug Coverage

After completing this application-based continuing education activity, pharmacists will be able to

Describe the different types of prescription drug coverage available to Medicare patients
Explain the patient costs associated with Medicare Part D prescription drug coverage
Demonstrate use of a patient’s Medicare Part D formulary to determine the appropriate type of coverage determination
Identify prescriptions that Medicare Part D does not cover

After completing this application-based continuing education activity, pharmacy technicians will be able to:

Describe the different types of prescription drug coverage available to Medicare patients
Explain the patient costs associated with Medicare Part D prescription drug coverage
Identify the types of coverage determinations available for Medicare Part D prescriptions
Outline the timeframes involved in Medicare Part D coverage determination and appeal decisions

Millions of Americans are enrolled in Medicare Part D, with hundreds of specific Part D plans available across the country. The Centers for Medicare & Medicaid Services (CMS) regulates Part D coverage. Part D plans must submit their plan costs and formularies, including formulary restrictions, to CMS for annual approval. Patient costs for Part D coverage vary based on the specific choice of plan and the benefit phase. All Part D plans must provide a process for requesting coverage of prescription medications that are not on the formulary or on the formulary with restrictions. Pharmacists and pharmacy technicians are valuable resources and can advise Part D patients and prescribers about prescription costs and the options available for non-covered medications.

INTRODUCTION

As of April 2023, more than 51 million Americans were enrolled in prescription drug coverage through Medicare, with the number of enrollees steadily increasing every year.¹Private insurance companies contracted by the Centers for Medicare & Medicaid Services (CMS) provide Medicare prescription drug coverage. Although specific plans’ details differ, CMS requires that all plans offer certain features.

Pharmacists and pharmacy technicians can assist patients in navigating these features to maximize their prescription benefits. This continuing education activity will review the types of Medicare prescription drug coverage, associated patient costs, formulary structure, and the options available when a patient’s Part D plan does not cover a medication.

MEDICARE AND PRESCRIPTION DRUG COVERAGE

CMS provides “Original Medicare” to most Americans aged 65 and older. Original Medicare includes²:

Part A: Most Americans are eligible for Medicare Part A at no additional cost, as long as they or their spouses have paid sufficient Medicare taxes. Medicare Part A includes coverage for inpatient hospital stays, hospice, and skilled nursing facility care.
Part B: Medicare Part B is optional and usually requires additional fees. Part B coverage includes outpatient and home health care, preventive services, and durable medical equipment.

CMS contracts with private insurance companies to provide prescription drug coverage. Individuals enrolled in Original Medicare may purchase a standalone Part D Prescription Drug plan (PDP) for outpatient prescription drug coverage.

Rather than using CMS coverage, individuals may purchase Medicare-approved private insurance called Medicare Advantage (MA), also known as Part C. With this arrangement, the MA Plan supersedes Medicare Part A and Part B for most coverage. MA plans often have lower patient costs and extra benefits compared to Original Medicare but may have fewer covered hospitals and physicians.² Medicare Advantage Prescription Drug (MAPD) plans are MA plans that include prescription drug coverage and eliminate the need for a separate PDP.

SIDEBAR: Patient Costs Defined

Monthly Premium: a monthly payment that maintains enrollment in the plan; not impacted by deductible, copay, or coinsurance amounts

Annual Deductible: a yearly dollar amount the patient pays before insurance starts to contribute

Copayment (or Copay): a specific, pre-determined dollar amount the patient pays for each prescription, office visit, or other type of care after satisfying the deductible

Coinsurance: an alternative to a copay, the percentage of the total cost the patient pays for each prescription, office visit, or other type of care after satisfying the deductible

Medicare plans are associated with various costs to the enrollee (see SIDEBAR: Patient Costs Defined). Individuals with income higher than a predefined threshold pay a higher premium for their Part B coverage due to Medicare’s Income Related Monthly Adjustment Amount (IRMAA). IRMAA does not change any of the other costs associated with Medicare coverage. CMS may also issue a late enrollment penalty (LEP) to people who do not sign up for Part D (from either a PDP or MAPD) as soon as they become eligible for Medicare. Once assigned, CMS adds the LEP to the patient’s monthly Part D premium for the remainder of their enrollment in Part D, regardless of which Part D plan they choose. Even people not actively taking prescription medications should consider choosing a Part D plan with a low monthly premium and/or no annual deductible to avoid incurring LEP.²

Individuals and couples with incomes and assets less than an annual threshold set by CMS may qualify for a Low Income Subsidy (LIS), also known as “extra help.” For people who qualify, the LIS reduces or eliminates the Part D monthly premium, deductible, and copay/coinsurance. CMS automatically enrolls most qualified patients into extra help, but a manual application process is also available. Pharmacy personnel should refer patients to 1-800-MEDICARE or https://www.medicare.gov/basics/costs/help/drug-costs to see if they qualify for LIS.³

Once a patient decides between Original Medicare or MAPD coverage, the next step is choosing a specific plan. CMS provides a comprehensive platform, called Medicare Plan Finder (MPF) for patients to shop and compare costs for PDP and MAPD plans. Patients can enter their medication list and see detailed cost information for each prescription. MPF also includes information about participating pharmacies and Star Ratings, a system CMS uses to measure each Part D plan’s performance in the areas of customer service, member experience, drug safety, and drug pricing accuracy. CMS rates plans on a scale of one to five stars, with five stars indicating the highest level of performance.⁴

The MPF tool is located at www.medicare.gov/plan-compare.

It is not necessary for pharmacy personnel to distinguish between MAPD and PDP coverage before processing prescription claims. The member’s prescription drug card provides the details needed to submit pharmacy claims to either type of Part D plan. If the member’s prescription drug card is not available, CMS provides a process known as an E1 transaction that returns Part D coverage information using basic demographic information. Pharmacists and technicians should consult their employer’s training materials for specific instructions on submitting an E1 transaction.⁵

The Part D Coverage Cycle

The Part D coverage cycle runs January to December each year. Regardless of when an individual reaches each phase of coverage, summarized in Figure 1, they start over in the deductible phase each year on January 1^st. Only “True Out-of-Pocket” (TrOOP) costs as defined by CMS go toward the thresholds to move patients through each of the four coverage phases. Patient costs excluded from TrOOP are⁶

Medications not covered by the Part D plan
Prescriptions obtained at non-participating (i.e., out-of-network [OON]) pharmacies, except those specifically allowed under the Part D plan’s rules
Costs reimbursed by an organization other than the Part D plan

PAUSE AND PONDER: Some patients with lower prescription costs do not complete their annual deductible until November or December. They are surprised when their out-of-pocket costs increase again in January. How would you explain the increase?

Patients with higher prescription costs may also be subject to the coverage gap, commonly known as the “Donut Hole” (see SIDEBAR: Explaining the Donut Hole). The coverage gap occurs when a patient’s prescription drug costs exceed a defined threshold under Medicare Part D. In the coverage gap, a patient’s out-of-pocket cost for brand name prescriptions may increase.⁷ Patients with very high prescription drug costs may reach the end of the coverage gap to enter catastrophic coverage, where they pay nothing out of pocket. The Inflation Reduction Act of 2022 removed patient costs from the catastrophic phase starting in 2024 and eliminated the coverage gap starting in 2025.⁸

SIDEBAR: Explaining the Donut Hole

Have you ever wondered why the Medicare Part D coverage gap is called the “Donut Hole?”

Imagine a giant donut, a circle with a hole in the middle, big enough to drive through. Half of the donut is plain, but the other half has frosting and sprinkles. In January, you start driving in a straight line through the plain half of the donut, toward the frosted half. Your drug costs determine your speed.

The plain half of the donut represents the annual deductible and initial coverage phases where you are subject to normal coverage amounts.

If high drug costs cause you to drive faster, you exit the plain half of the donut and enter the donut’s hole before the end of the year. You are now driving where there is no donut, and you must pay more than the normal amount for brand name drugs.

If your drug costs are high enough that you speed to the other side of the hole before the end of the year, then you enter the frosting and sprinkles half of the donut. Frosting and sprinkles represent the additional Part D contributions in the catastrophic phase and you pay nothing out of pocket.

Unfortunately, your car has only a 365-day warranty, so when January comes, you must start all over at the plain side of the donut.

An annual bidding process determines the specific costs for each Part D plan. Each year, CMS sets limits and thresholds for certain aspects of Part D coverage but allows flexibility within these parameters for both PDP and MAPD plans. Insurance companies submit bids that demonstrate how their plans comply with CMS’s annual limits and thresholds. The financial information that contributes to each plan’s annual bid is highly complex, and CMS can either accept or reject each bid.

As part of the annual bidding process, CMS defines standard prescription drug coverage. For a “basic” Part D plan, a bid must either match or be financially equivalent to the CMS definition of standard coverage. Table 1 provides the 2023 and 2024 standard benefit parameters, as defined by CMS.⁹

Table 1. Limits and Thresholds for 2023 and 2024 Medicare Part D Plans⁹

	2023	2024
Annual Deductible Limit	$505	$545
Initial Coverage Limit (starts the coverage gap)	$4660 total drug costs	$5030 total drug costs
Out-of-Pocket Limit (ends the coverage gap and starts catastrophic phase)	$7400 patient cost	$8000 patient cost

Insurance companies may also offer “enhanced” Part D plans with coverage that is more robust than the defined standard. Most plans with enhanced coverage have higher monthly premiums compared to basic plans but offer corresponding advantages such as reduced deductibles, lower copays/coinsurance, and lower costs in the coverage gap.

Individuals should choose their Part D plans carefully because they can only sign up or change Part D plans during certain periods²:

During the 3-month initial enrollment period that starts 1 month before and ends 1 month after an individual’s 65^th birthday; coverage starts the month after initial enrollment
During the annual open enrollment period that runs from mid-October to early December each year; coverage starts on January 1 of the following year for people who enroll during annual open enrollment
During the Medicare Advantage open enrollment period that runs from January through March each year; during this time, CMS only allows certain types of changes
During special enrollment periods for qualifying events such as relocation or the loss of employer or Medicaid coverage. Natural disasters that disrupt the initial or annual enrollment period may also create special enrollment periods

Prescription Coverage Under Medicare Parts A and B

Original Medicare provides prescription drug coverage under very limited circumstances and CMS prohibits Part D from covering anything covered under Medicare Parts A or B.

Medicare Part A covers hospice care, including medications related to the hospice diagnosis. Hospice providers receive payment for these medications from CMS and are responsible for paying the pharmacy. Medicare Part D is prohibited from covering medications related to any hospice diagnosis.¹⁰

Medicare Part B provides the only coverage options for some items, such as diabetic testing supplies and certain vaccines. Coverage for other items may fall under Part B or Part D, depending on the specific circumstances. Table 2 compares Part B and Part D coverage for the most common examples.¹⁰

Table 2. Medicare Part B and Part D Coverage of Common Products

Product(s)	Part B Coverage	Part D Coverage^a
Nebulizer Solutions (such as albuterol sulfate and ipratropium bromide)	For patients residing at home.	For patients residing in a long-term care facility.
Influenza, Hepatitis B, Pneumonia, and Coronavirus (COVID-19) Vaccines	Yes	No
Immunosuppressants (such as cyclosporine and mycophenolate mofetil)	When used to prevent rejection of a Medicare-covered transplant.	When used for a medically accepted indication other than a Medicare-covered transplant.
Oral Anti-Cancer Drugs (such as cyclophosphamide and methotrexate)	When used to treat cancer.	When used to treat a medically accepted indication other than cancer.
Oral Anti-Emetic Drugs (such as ondansetron and promethazine)	When used to treat or prevent chemotherapy-related nausea and vomiting.	When used to treat or prevent medically accepted indications other than chemotherapy-related nausea and vomiting.
Insulin	When used in an insulin pump.	When not used in an insulin pump.
Diabetic Testing Supplies (such as test strips and lancets)	Yes	No
Insulin Injection Supplies (such as needles and alcohol swabs)	No	Yes
^aCoverage may be subject to formulary restrictions.

Part D plans are responsible for rejecting pharmacy claims for medications that may be covered under Part A or Part B. Pharmacy personnel should refer to claim reject messaging and redirect the claim appropriately.

Other Prescription Drug Coverage

Most people who qualify for Medicare are covered by some combination of Parts A, B, C, and D as described above. However, other prescription drug coverage options are available under special circumstances:

Employer Group Waiver plans (EGWPs): Employers may choose to provide prescription drug coverage for their retirees by contracting with a Part D plan for EGWP coverage. Retirees with EGWP plans that start as soon as they become eligible for Medicare are exempt from LEP. When providing an EGWP plan for their retirees, employers may also add additional benefits paid either through Part D or by the employer themselves.¹¹
Medicare Supplemental Insurance (Medigap): Medigap coverage helps with costs not covered by Medicare Parts A and B, such as copays and deductibles. Certain Medigap plans also help with skilled nursing facility or hospice costs and emergency care while traveling outside of the United States. Individuals who enrolled in Medigap prior to 2006 may have prescription drug coverage included, but those who are newer to Medigap should purchase separate Part D coverage to avoid LEP.¹²
Employer Coverage: Individuals who are actively employed (not retired) may have coverage through their employer to replace Medicare or use Medicare as secondary coverage. Covered employees are exempt from the LEP if the employer coverage is equivalent to at least a basic Part D plan.²
Consolidated Omnibus Budget Reconciliation Act (COBRA): People who have recently separated from an employer may be eligible for COBRA. Individuals enrolled in COBRA may still be subject to LEP because COBRA is usually not equivalent to Medicare coverage.²
Medicaid: People with low incomes who qualify for both Medicaid and Medicare receive the LIS and have Part D coverage with reduced patient costs. In most cases, Medicare pays first and Medicaid helps with remaining costs.²
Manufacturer Discount Programs: Many drug manufacturers provide coupons, discount cards, and patient assistance programs to help cover their products’ cost. Federal law prohibits using these manufacturer payments in combination with Medicare prescription drug coverage.¹³ Medicare patients may choose manufacturer coupons or patient assistance programs for certain prescriptions only when they do not use their Part D coverage.
Prescription Discount Cards: Unlike manufacturer discounts, which are limited to products produced by that manufacturer, prescription discount cards offer discounts on a wide range of medications. Also known as “cash cards”, prescription discount cards reduce the cash price of prescriptions, but are not used in combination with insurance, including Medicare.¹⁴ Patients who choose a prescription discount card cannot use it in combination with their Part D coverage for the same medication.

MEDICARE PART D FORMULARIES

CMS requires Part D plans to maintain a list of covered drugs, called a formulary. CMS reviews each Part D formulary to ensure sufficient coverage under each drug class. The copay or coinsurance for each medication on the formulary is determined by its “tier.” Medications on lower tiers generally cost less than drugs on higher tiers.¹⁵ CMS allows some flexibility on how Part D plans define their formulary tiers, so tier structure differs between plans. Figure 2 provides an example of a formulary tier arrangement.

Drug Placement and Formulary Restrictions

Specialty medications are high-cost prescription products used to treat complicated medical conditions. CMS limits the patient cost portion for these medications and Part D plans typically place all specialty mediations into designated formulary tiers.¹⁰

CMS requires that Part D plans cover adult vaccines (excluding those covered under Part B) recommended by The Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices at no cost to the patient, regardless of formulary tier or benefit phase.¹⁶

In 2023, CMS began setting a maximum copay for insulin products covered under Part D. Currently, the maximum copay is $35 for a one-month supply and is subject to change on an annual basis. Insulin copays may be lower if a Part D plan includes specific insulin products on a formulary tier where the monthly copay is lower than the CMS maximum. A similar program exists for insulin used in an insulin pump and covered under Part B.¹⁶

Part D plans may put restrictions on formulary medications to ensure appropriate coverage and to control costs. CMS reviews the restrictions and will not allow overly restrictive formularies. Plans may place four types of restrictions on formulary medications¹⁰:

Quantity Limit: Quantity limit restrictions define the maximum number of dosage units allowed for a specific time period.
Step Therapy: Step therapy restrictions require patients to first try a different medication, usually a lower cost alternative, before the prescribed medication.
Prior Authorization: Prior authorizations require patients to meet specific criteria, which may be as simple as providing the diagnosis or more complicated (e.g., specific lab tests, involvement of a specialist physician).
Drug Utilization Review (DUR): May be “hard edits” that require a coverage determination or “soft edits” that require the dispensing pharmacist to obtain clinical information and enter a set of codes into the prescription claim.

CMS defines six drug classes—those used to treat disorders where changes or interruptions in therapy involve higher risk—as “protected class.” CMS requires that Part D formularies include most medications within these classes with at least one medication on a preferred tier and no restrictions. Plans are not, however, required to include all variations of each medication (i.e., brand name and generic or immediate and extended-release versions). The six protected classes are¹⁰

immunosuppressants (used to prevent organ transplant rejection)
antidepressants (used to treat depression)
antipsychotics (used to treat mental health disorders)
anticonvulsants (used to treat seizure disorders)
antiretrovirals (used to treat human immunodeficiency virus)
antineoplastics (used to treat cancer)

CMS allows plans to add medications and make other positive changes to their formulary throughout the year but restricts medication removal and other negative changes until the following January. This restriction protects patients from losing coverage for their prescriptions during the time when they cannot switch to a different Part D plan. Marketplace removal, safety concerns, and the availability of a new generic are examples of situations when CMS would allow removal of a medication from a Part D formulary during the year.

Part D plans must provide patients with ongoing access to their formulary information. Most Part D plans post formularies online and only provide paper copies upon request. Patients can also see the formulary status for their specific medications when comparing Part D plans using the MPF website.

COVERAGE DETERMINATIONS AND APPEALS

Patients and pharmacy personnel commonly generalize the term “prior authorization” to describe any situation that requires insurance approval before insurance covers a prescription. Under Medicare Part D, this is known as the coverage determination process. Part D patients may use the coverage determination process to request approval for a non-formulary medication or a formulary medication with restrictions.

Who hasn’t been frustrated after contacting a prescriber to change a non-formulary prescription to a formulary medication, only to have the formulary medication require prior authorization? Part D plans usually include messaging within rejected claims to help determine which type of coverage determination is needed. When faced with a prescription rejection, pharmacists and pharmacy technicians who understand the nuances of the coverage determination process are equipped to advise their Part D patients on the best course of action.

Several specific types of coverage determinations are available and each type of coverage determination has specific criteria for approval.^16,17 Table 3 provides a summary of coverage determination types, their uses, and the information required for approval.

Table 3. Types of Coverage Determinations and Their Uses^16,17

Medication Status	Coverage Determination	Requirements for Approval
On the formulary, but dosing regimen requires more than the formulary allowance or requires tablet splitting	Quantity Limit Exception	The quantity allowed by the plan’s formulary is not effective in treating the patient’s condition or requires tablet-splitting to achieve the prescribed dosing regimen.
On the formulary with step therapy restrictions	Step Therapy Exception	The patient tried the step medication and either did not achieve therapeutic effect or experienced an adverse outcome.
On the formulary with step therapy restrictions	Step Therapy	The patient is likely to experience an adverse outcome if they must first try the step medication.
On the formulary with prior authorization or “hard” DUR restrictions	Prior Authorization	The patient meets the Part D plan’s specific criteria for the prescribed medication.
On the formulary with a “soft” DUR restriction	None	DUR “soft edits” may require dispensing pharmacists to contact prescribers and obtain clinical information, but do not require a coverage determination.
Sometimes by Medicare Part B	Prior Authorization	Why the patient’s situation warrants coverage under Part D for the prescribed medication.
On the formulary, but the patient cannot afford the copay/coinsurance	Tier Exception	The required number^† of lower tier drugs for the same condition are less effective or likely to result in an adverse outcome. Not available for specialty or non-formulary medications and cannot provide a brand name medication at the generic cost.
Not on the formulary	Non-formulary Exception	The required number^† of formulary alternative medication(s) were ineffective or likely to result in an adverse outcome.

^†Patients should consult their specific plan information to find out how many alternatives are required for tier or non-formulary exceptions.

Part D plans will only approve a coverage determination request if the product is medically necessary and if the information submitted by the prescriber meets the plan’s criteria. Prescribers may submit information over the phone, by fax, or by mail. Most Part D plans also have an electronic portal to accept information from prescribers. Dispensing pharmacists are only permitted to supply information in place of the prescriber under limited circumstances, such as prior authorizations to determine Part B versus Part D coverage.

Approval and Denial Parameters

For exception requests that meet approval criteria, CMS requires Part D plans to maintain the approval at least through the end of the year. Part D plans may approve prior authorizations for a shorter time only if clinically appropriate and approved by CMS as part of the annual formulary approval process.

Part D plans will deny requests with incomplete information and requests that do not meet approval criteria. Part D plans will also deny any type of coverage determination if the medication is being used for a non-medically accepted indication. Medically accepted indications are uses approved by the United States Food and Drug Administration or listed in one of the references that CMS defines as approved compendia¹⁰:

American Hospital Formulary Service Drug Information
DRUGDEX Information System
Peer-reviewed medical literature (only allowed for biologics and anti-cancer chemotherapy medications)

Common examples of medications prescribed for non-medically accepted indications include the use of fentanyl lollipops/lozenges for non-cancer pain and hydroxychloroquine for coronavirus disease 2019 (COVID-19). Federal and state laws may allow prescriptions for non-medically accepted indications, but patients cannot use their Part D coverage to pay for them. Part D plans must block medication coverage if the determination process reveals a non-medically accepted indication, even for previously covered medications, quantities less than the predetermined limit, and any tier cost after a tier exception request.¹⁰ Pharmacists are not required to confirm medically accepted indications before dispensing prescriptions because CMS considers this a plan responsibility. As a result, Part D plans will often reject claims and require a prior authorization for medications commonly prescribed for non-medically accepted indications. Pharmacists and pharmacy technicians can assist patients and prescribers by communicating rejected claim information and explaining the CMS requirement for medically accepted indications. ¹⁰

In addition to medications covered under Part A or B, CMS specifically excludes certain types of medications from Part D coverage¹⁰:

Products used for weight loss or weight gain
Fertility medications
Cosmetic and hair growth products
Treatments for the symptomatic relief of cough and colds
Non-prescription medications
Prescription vitamins, except prenatal and fluoride products
Erectile dysfunction treatments

Bulk powders and inert excipients used for compounded prescriptions are also excluded from Part D coverage. Compounds may contain other ingredients that are covered with or without restrictions under Part D. When pharmacies bill some of a compound’s ingredients to Part D, CMS prohibits them from charging patients for the non-Part D portion.¹⁰

Patients cannot obtain Part D coverage for excluded medications using the coverage determination process. Employers may cover some of these medications and manufacturer coupons or prescription discount cards may help make these products more affordable for individuals without employer coverage.

PAUSE AND PONDER: Generic sildenafil is prescribed for both erectile dysfunction (excluded from Part D coverage) and pulmonary hypertension (eligible for Part D coverage). Can a dispensing pharmacist distinguish between the two to bill Part D for the appropriate product?

Part D plans may dismiss requests that are inappropriate, unnecessary, or filed incorrectly. CMS requires Part D plans to provide written notification and a reason for the dismissal to the patient and prescriber.¹⁷

If the patient or prescriber decides that a request is unnecessary, they can withdraw the request before a decision is issued. Withdrawing a request does not prevent the patient or prescriber from submitting a later request for the same medication.¹⁷

When a Part D plan denies a coverage determination, CMS requires them to send the specific reason(s) for the denial to the patient and the prescriber. Part D plans may choose to also send a copy of this information to the dispensing pharmacy.¹⁷ Depending on the reason for the denial, the patient or prescriber may choose to appeal the Part D plan’s decision.

Appeal requests must be within 60 days of the denial, unless good cause is established for missing the 60-day deadline. If the Part D plan denies the appeal, beneficiaries have up to four additional opportunities to appeal through entities outside of their Part D plan. After the second level, higher levels of appeal are only available if the drug cost meets a specific threshold set by CMS.¹⁸ Figure 3 outlines the five levels of appeal available to Part D patients.

A patient or prescriber can request a re-opening instead of the next level appeal if they feel that a coverage determination or appeal decision is in error. Part D plans may also initiate a re-opening if they identify a decision error.

Direct Member Reimbursements

Patients who pay for a covered Part D prescription without using their Part D Insurance may be eligible for reimbursement from their Part D plan through a process called Direct Member Reimbursement (DMR). To qualify for DMR, the prescription must meet the Part D plan’s coverage requirements and not be covered by any other type of insurance or discount card. Prescriptions obtained at an OON pharmacy must meet the Part D plan’s OON rules to qualify for reimbursement.¹⁹

Pharmacies should submit Part D prescriptions to the patient’s Part D plan whenever possible because a DMR reimbursement may not result in a full refund of the cash price.

Timeframes

Part D plans must offer both standard and expedited timeframes for coverage determination and appeal requests (listed in Table 4). Expedited requests are available when the standard timeframe could result in a significant adverse outcome. DMR requests do not qualify for expedited timeframes because the patient has already received the medication.¹⁷

Table 4. Plan Timeframes for Medicare Part D Requests¹⁶

Request Level	Request Urgency	Request Type	Required Timeframe
Initial Coverage Determination	Standard	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception	72 hours from supporting statement but no longer than 14 days from request received
Initial Coverage Determination	Expedited	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception	24 hours from supporting statement but no longer than 14 days from request received
Initial Coverage Determination	Standard	Prior Authorization Step Therapy (non-exception)	72 hours from request received
Initial Coverage Determination	Expedited	Prior Authorization Step Therapy (non-exception)	24 hours from request received
Initial Coverage Determination	N/A	Direct Member Reimbursement	14 days from request received
First Level Appeal	Standard	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception Prior Authorization	7 days from request received
First Level Appeal	Expedited	Quantity Limit Exception Step Therapy Exception Tier Exception Non-Formulary Exception Prior Authorization	72 hours from request received
First Level Appeal	N/A	Direct Member Reimbursement	Notification of Decision: 14 days from request received Payment (if approved): 30 days from request received

Part D plans may automatically apply the expedited timeframe if the clinical information submitted for the coverage determination indicates that waiting may harm the patient’s health. Alternatively, Part D plans may downgrade an expedited request if they determine that the patient’s health will not be harmed by using the standard timeframe. CMS requires Part D plans to notify the patient if a request is downgraded from expedited to standard.¹⁷

All Part D timeframes are based on calendar hours/days and include weekends and holidays. Timeframes start as soon as the Part D plan receives a non-exception coverage determination or any type of valid appeal request, regardless of how much clinical information is included with the request. For exception requests, the timeframe starts as soon as the Part D plan receives clinical information from the prescriber to support the request (known as the prescriber’s supporting statement). When a supporting statement is missing from an exception request, CMS allows up to 14 days for plans to obtain it.¹⁷The following examples demonstrate Part D timeframes over weekends and holidays:

A patient requests a standard prior authorization on Friday afternoon, December 23. The prescriber’s office is closed for the three-day holiday weekend. The plan must deny the request in 72 hours (on Monday afternoon), even though the prescriber’s office was not available to provide information during that timeframe.
A different patient requests a standard non-formulary exception the same day. Their prescriber’s office is also closed for the three-day holiday weekend but contacts the plan with the supporting information on Tuesday morning. Since this is an exception request, 72 hour timeframe starts on Tuesday morning and the plan has until Friday morning to complete the request.

When clinical information is incomplete, CMS requires that Part D plans make reasonable efforts to contact the prescriber and obtain the missing information. Once the timeframe has started, making outreach attempts and waiting for additional information does not extend the request timeframe. The Part D plan will deny the request if they do not receive sufficient clinical information by the end of the allotted timeframe.¹⁷

PAUSE AND PONDER: It’s late Friday afternoon and your patient is anxious to request a prior authorization for her medication. The physician’s office is closed for the weekend. Could requesting an expedited coverage determination at this point cause more of a delay?

When a Part D plan does not process a request within the required timeframe, they must send the request to the IRE as an “auto-forward.” This is the same IRE that processes Part D second-level appeals. Part D plans must notify patients in the event of an auto-forward. CMS monitors Part D plans’ timeliness and issues penalties for excessive numbers of auto-forwards.

How to Submit Requests

CMS requires that Part D plans accept coverage determination requests via phone, fax, or mail. For appeals, plans must accept both standard and expedited requests via fax or mail. Verbal requests by phone are required for expedited appeals but optional for standard appeals.¹⁷ Many plans also choose to accept electronic requests via an online portal.

Patients should follow the instructions from their specific Part D plan for requesting a DMR. Part D plans usually require hard copies of payment receipts, so most patients file DMR requests by mail.

CMS does not permit Part D plans to require a specific form to submit a coverage determination, appeal, or DMR request.¹⁷ Although optional, using a form provided by the plan usually streamlines the process and reduces the risk of submitting incomplete information.

CMS does not allow dispensing pharmacists or pharmacy technicians to request a Part D coverage determination or appeal on behalf of the patient. Only the patient, the patient’s appointed representative, the prescriber, or the prescriber’s staff can request a coverage determination or appeal. Only patients or their appointed representative can request a DMR.¹⁷

The handout entitled “Medicare Prescription Drug Coverage and Your Rights” that dispensing pharmacies supply to patients when prescriptions cannot be filled under their Part D plan provides additional instructions for submitting requests.^17,20

CONCLUSION

Medicare patients have many choices available for their prescription drug coverage. CMS requires that all Part D plans conform to a set of common standards while allowing specific plans to offer a wide range of benefit options.

Pharmacists and pharmacy technicians with a basic understanding of Part D coverage options, patient costs, formulary structure, and the coverage determination and appeals process can help patients maximize the benefit from their Part D plan. Although CMS does not allow them to initiate coverage determinations and appeals, pharmacy personnel can advise Part D patients and their physicians on the most effective next steps when faced with a non-covered prescription.

All “Prior Authorizations” are Not Created Equal: A Guide to Medicare Part D Prescription Drug Coverage

Pharmacists Post-test

After completing this continuing education activity, pharmacists will be able to
1. Describe the different types of prescription drug coverage available to Medicare patients.
2. Explain the patient costs associated with Medicare Part D prescription drug coverage.
3. Demonstrate use of a patient’s Medicare Part D formulary to determine the appropriate type of coverage determination.
4. Identify prescriptions that Medicare Part D does not cover.

1. Which of the following is the correct description for the type of Medicare coverage?
A. Medicare Part A: Covers outpatient and home health care, preventative services, and durable medical equipment.
B. Medicare Part B: Offered by private insurance companies for prescription drug coverage.
C. Medicare Part C: Offered by private insurance companies to provide Part A and Part B coverage.

2. What is an appropriate combination of coverage?
A. Medicare Part A + Medicare Part B + Medicare Part D
B. Medicare Part A + Medicare Part B + MAPD
C. Employer Coverage + Medigap + MAPD

3. A patient who is turning 65 next month asks you about delaying Part D coverage because she only takes two prescriptions that are very low cost using a prescription discount card. What is the possible risk of this approach when she eventually signs up for Part D coverage at a later date?
A. She may pay higher monthly premiums due to the coverage gap.
B. She may pay higher annual deductibles due to the late enrollment penalty.
C. She may pay higher monthly premiums due to the late enrollment penalty.

4. It’s January and a patient who paid a $10 copay for his prescription last month now has to pay 100% of the cost. What is the most likely explanation?
A. He is paying the annual deductible
B. He is in the coverage gap
C. His Part D plan doesn’t cover his medication

5. A patient who takes several expensive medications experiences a sharp increase in her out-of-pocket costs around midyear. What is the most likely explanation?
A. She has entered the deductible phase
B. She has entered the coverage gap phase
C. She has entered the catastrophic coverage phase

6. A patient’s Part D Plan is rejecting a prescription for apixaban. You locate its formulary online and find that dabigatran is listed, but not apixaban. What type of coverage determination does this patient need from this Part D Plan?
A. Step Therapy
B. Non-formulary
C. Prior Authorization

7. A patient’s Part D Plans is rejecting a prescription for alirocumab. You locate the formulary online and find that alirocumab is on the formulary but is not covered unless simvastatin has been tried first. What type of coverage determination does this patient need from this Part D Plan?
A. Step Therapy
B. Prior Authorization
C. Tier Exception

8. A Part D patient is struggling to afford his medication, even after the Part D Plan approved a non-formulary exception. What is their best option for lowering costs?
A. Talk to the prescriber about switching to an alternative on a lower formulary tier.
B. Ask their Part D Plan for a tier exception.
C. Find a manufacturer discount coupon to cover their Part D copay.

9. A Part D patient presents a prescription for a highly advertised diabetic medication and confides in you that she is not diabetic but hoping the medication will help with weight loss. Her Part D Plan requires prior authorization to establish medically accepted indication. What coverage option is available to them?
A. Part D after prior authorization approval
B. Manufacturer discount program
C. Medicare Advantage

10. A Medicare Part D Plan is rejecting claims for your patient’s diabetic test strips and lancets. What do you recommend as the next course of action?
A. Call the Part D Plan and request a coverage determination.
B. Pay out of pocket and ask the Part D Plan for direct member reimbursement.
C. Compile the documentation required to submit the claims to Part B.

All “Prior Authorizations” are Not Created Equal: A Guide to Medicare Part D Prescription Drug Coverage

Pharmacy Technician Post-test

After completing this continuing education activity, pharmacy technicians will be able to
1. Describe the different types of prescription drug coverage available to Medicare patients.
2. Explain the patient costs associated with Medicare Part D prescription drug coverage.
3. Identify the types of coverage determinations available for Medicare Part D prescriptions.
4. Outline the timeframes involved in Medicare Part D coverage determination and appeal decisions.

2. What is an appropriate combination of coverage?
A. Medicare Part A + Medicare Part B + Medicare Part D
B. Medicare Part A + Medicare Part B + MAPD
C. Employer Coverage + MAPD

5. A patient who takes several expensive medications experiences a sharp increase in her out-of-pocket costs around midyear. What is the most likely explanation?
A. She has entered the deductible phase.
B. She has entered the coverage gap phase.
C. She has entered the catastrophic coverage phase.

6. Which of the following combinations of coverage determinations may be required for a single prescription?
A. Non-formulary + Quantity Limit
B. Quantity Limit + Prior Authorization
C. Tier Exception + Non-formulary

7. Which type of reject requires a Part D coverage determination?
A. Non-formulary
B. Refill too soon
C. DUR soft edit

8. Which of the following is the correct description for a type of coverage determination under Medicare Part D?
A. Non-formulary exceptions: Used to request larger quantities of a medication
B. Tier Exceptions: Used to request a lower copay for a medication
C. Prior Authorization: Used to request a non-formulary medication

9. A patient called her Part D plan yesterday morning to request an urgent appeal for their medication. This afternoon, she has not received a response and the claim is still rejecting. How much longer might she have to wait for a response?
A. The appeal is already out of timeframe because it has been longer than 24 hours
B. 6 more days, for a total of 7 days
C. 2 more days, for a total of 3 days

10. You are working on a prescription that the Part D Plan is rejecting due to a quantity limit. The patient is not out of medication, so you advise him to call and ask for a standard quantity limit exception. How long should the patient expect to wait for the Part D Plan to make a decision?
A. 24 hours after the patient calls their Part D Plan to request the coverage determination
B. 24 hours after their prescriber provides clinical information to the Part D Plan
C. 72 hours after their prescriber provides clinical information to the Part D Plan

References

1. Centers for Medicare & Medicaid Services. Medicare Enrollment Dashboard. Accessed August 28, 2023. https://data.cms.gov/tools/medicare-enrollment-dashboard
2. Centers for Medicare & Medicaid Services. Medicare & You Handbook. Accessed September 5, 2023. https://www.medicare.gov/medicare-and-you
3. Centers for Medicare & Medicaid Services. Help with Drug Costs. Accessed September 6, 2023. https://www.medicare.gov/basics/costs/help/drug-costs
4. Centers for Medicare & Medicaid Services. Explore Your Medicare Coverage Options. Accessed September 13, 2023. www.medicare.gov/plan-compare
5. RelayHealth. Medicare Eligibility Verification Transaction. Accessed December 28, 2023. https://medifacd.mckesson.com/e1/
6. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 5: Benefits and Beneficiary Protections. September 20, 2011. Accessed September 5, 2023. https://www.cms.gov/medicare/prescription-drug-coverage/prescriptiondrugcovcontra/downloads/memopdbmanualchapter5_093011.pdf
7. Centers for Medicare & Medicaid Services. Costs in the Coverage Gap. Accessed September 6, 2023. https://www.medicare.gov/drug-coverage-part-d/costs-for-medicare-drug-coverage/costs-in-the-coverage-gap
8. Kaiser Family Foundation. Changes to Medicare Part D in 2024 and 2025 Under the Inflation Reduction Act and How Enrollees Will Benefit. Accessed December 27, 2023. https://www.kff.org/medicare/issue-brief/changes-to-medicare-part-d-in-2024-and-2025-under-the-inflation-reduction-act-and-how-enrollees-will-benefit
9. Centers for Medicare & Medicaid Services. Announcement of Calendar Year (CY) 2024 Medicare Advantage (MA) Capitation Rates and Part C and Part D Payment Policies. March 31, 2023. Accessed September 6, 2023. https://www.cms.gov/files/document/2024-announcement-pdf.pdf
10. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 6 – Part D Drugs and Formulary Requirements. January 15, 2026. Accessed August 23, 2023. https://www.cms.gov/medicare/prescription-drug-coverage/prescriptiondrugcovcontra/downloads/part-d-benefits-manual-chapter-6.pdf
11. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 12 – Employer/Union Sponsored Group Health plans. November 7, 2008. Accessed September 5, 2023. https://www.cms.gov/regulations-and-guidance/guidance/transmittals/downloads/dwnlds/r6pdbpdfpdf
12. Centers for Medicare & Medicaid Services. Learn How Medigap Works. Accessed October 25, 2023. https://www.medicare.gov/health-drug-plans/medigap/basics/how-medigap-works
13. Office of Inspector General. Special Advisory Bulletin, Pharmaceutical Manufacturer Copayment Coupons. September 2014. Accessed September 5, 2023. https://oig.hhs.gov/documents/special-advisory-bulletins/878/SAB_Copayment_Coupons.pdf
14. Dr Christina Polomoff discusses the complex world of medication discount cards. Am J Manag Care. April 13, 2021. Accessed September 5, 2023. www.ajmc.com/view/dr-christina-polomoff-discusses-the-complex-world-of-medication-discount-cards
15. Centers for Medicare & Medicaid Services. What Medicare Pat D plans Cover. Accessed September 7, 2023. https://www.medicare.gov/drug-coverage-part-d/what-medicare-part-d-drug-plans-cover
16. Centers for Medicare & Medicaid Services. Final Contract Year (CY) 2024 Part D Bidding Instructions. April 4, 2023. Accessed September 6, 2023. https://www.cms.gov/files/document/final-cy-2024-part-d-bidding-instructions.pdf
17. Centers for Medicare & Medicaid Services. Parts C&D Enrollee Grievances, Organization/Coverage Determinations, and Appeals Guidance. August 3, 2022. Accessed September 10, 2023. https://www.cms.gov/medicare/appeals-and-grievances/mmcag/downloads/parts-c-and-d-enrollee-grievances-organization-coverage-determinations-and-appeals-guidance.pdf
18. Centers for Medicare & Medicaid Services. Medicare Appeals. Accessed August 23, 2023. https://www.medicare.gov/Pubs/pdf/11525-Medicare-Appeals.pdf
19. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Benefit Manual Chapter 14 – Coordination of Benefits. September 17, 2018. Accessed September 11, 2023. https://www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/Downloads/Chapter-14-Coordination-of-Benefits-v09-14-2018.pdf
20. Centers for Medicare & Medicaid Services. Medicare Prescription Drug Coverage and Your Rights. Accessed September 12, 2023. https://www.cms.gov/outreach-and-education/outreach/partnerships/downloads/yourrightsfactsheet.pdf

Patient Safety: Herbal Products and Potential Organ Dysfunction

After completing this application-based continuing education activity, pharmacists will be able to

List herbal products associated with liver, kidney, and heart damage

Describe potential drug interactions with herbal medications

Discuss the potential for contaminants in herbal products

After completing this application-based continuing education activity, pharmacy technicians will be able to

List herbal products associated with liver, kidney, and heart damage

Recognize the potential for herbal products to be unsafe

Describe certificates of analysis and how to retrieve them from manufacturers

As part of complementary and alternative medicine, herbal products are gaining popularity in the United States. Approximately one in five Americans use herbal products. Although people may perceive them as harmless due to their "natural" origin, studies and case reports on herbal toxicity dispute that belief. Injuries to liver, kidney, and heart; herb-drug interactions; and contamination and mislabeling are grave health risk concerns with some herbal products. Although non-prescription, herbal products' ubiquitous presence in all kinds of
shops, pharmacies, and Internet vendors causes many people to consider them important to their overall well-being. Pharmacists and technicians can help patients reduce health risks associated with herbal products. Ample knowledge of popular herbal products will help pharmacy teams identify health risks quickly.

Herbal Products and Health Risks

Pharmacist Post-test

After completing this continuing education activity, pharmacists will be able to
• List herbal products associated with liver, kidney and heart damage
• Describe potential drug interactions with herbal medications
• Discuss the potential for contaminants in herbal products

1. Which of the following agencies reviews and inspects herbal products before coming to market?
A. United States Food and Drug Administration
B. National Center for Complementary and Alternative Medicine
C. International Association of Traditional Chinese Medicine

2. John Goodman, a frequent customer at your pharmacy, comes to the counter to pick up his monthly medications. He asks, “Would it be a bother to have you check out the rest of my items here as well?” Always one to help a customer, you tell him, “Of course, that’s fine!” You notice he has a botanic extract tincture that claims to help with heartburn. The ingredient list includes greater celandine (Chelidonium majus). Mr. Goodman is also picking up his 30-day supply of Questran (cholestyramine). What organ dysfunction could be a concern?
A. Liver injury
B. Kidney injury
C. Heart damage

3. A patient presents to the emergency room suffering from acute kidney injury and liver injury. Lab tests show glutathione depletion, and the physician recommends N-acetylcysteine as a possible antidote. Upon opening the patient’s bag, you notice three natural product supplements: pennyroyal essential oils, germander weight loss tea, and impila fertility boost capsules. Which product may be responsible for BOTH the kidney and liver injury?
A. Pennyroyal essential oils
B. Germander weight loss tea
C. Impila fertility boost capsules

4. Mr. Goodman returns to your pharmacy. He explains he has been trying to live a healthier lifestyle, but has been feeling exceptionally tired after taking his as-needed alprazolam. When asked what over-the-counter products he uses, Mr. Goodman tells you, “Oh, you know the usual stuff: echinacea, garlic, ginger…” You are concerned because an interaction between alprazolam and ______ could be causing the excessive drowsiness.
A. Echinacea
B. Garlic
C. Ginger

5. Johnathan Bravo comes to the counter with a melancholic look on his face. “You know… getting older is not easy, especially when your wife looks so much better than you. I have tried everything: gym, new haircut, self-help books; and nothing seems to work.” He then proceeds to tell you about this supplement used in Southeast Kazakhstan that his gym buddy recommended. “Yeah, he says he’s seen guys lose weight, look better than ever and… well… you know… have a better relationship with their wife.” This sounds too good to be true; you are concerned this product has been _____________.
A. Mishandled
B. Mistaken
C. Mislabeled

6. Which of the following are chemists mainly concerned about when they look for contaminants in herbal products?
A. Metal
B. Glutathione
C. Poisons

7. Which of the following patients is most at risk of a serious adverse event associated with henbane (Hyoscyamus niger)?
A. A 27-year-old female with an irregular menstrual cycle
B. A 48-year-old male with a history of atrial fibrillation
C. A 62-year-old male with new onset major depressive disorder

8. Mrs. Jin is a longtime customer of your pharmacy who is on warfarin therapy for her atrial fibrillation. Her dose has been stable for quite some time, but today, you are surprised to see a change to her warfarin dosing. You call her cardiologist to double check the prescription and she tells you, “Yeah, it’s really crazy; three years no change in INR and out of nowhere a 0.2-point decrease.” Upon picking up her prescription, you ask Mrs. Jin about complementary and alternative medicine use. What herbal supplement might be a possible explanation for Mrs. Jin’s INR decrease?
A. Chamomile
B. Kava kava
C. American ginseng

9. “These kids nowadays takin’ that codeine, and that awful dextromethorphan!” exclaimed Mr. O’Timer. “When I was a kid, and even now, all I ever took was licorice. My mom, bless her soul, would never let any poison enter MY body. To this day that’s all I use when I get a cold.” Trying to move him along before he inevitably tries to talk to you about politics, you stop as he mentions his busy day full of specialist appointments. Which specialist would be MOST LIKELY to know Mr. O’Timer is using licorice for his colds?
A. Dentist
B. Podiatrist
C. Cardiologist

10. Which of the following patients would be at greatest risk if they accidentally took Asian ginseng instead of American ginseng?
A. A 23-year-old female taking fluvoxamine for obsessive compulsive disorder
B. A 40-year-old female taking ondansetron for chemotherapy-induced nausea
C. A 67-year-old male taking clopidogrel after a myocardial infarction

Pharmacy Technician Post-test

After completing this continuing education activity, pharmacy technicians will be able to
• List herbal products associated with liver, kidney and heart damage
• Recognize the potential for herbal products to be unsafe
• Describe certificates of analysis and how to retrieve them from manufacturers

1. Which of the following agencies review and inspect herbal products before coming to market?
A. United States Food and Drug Administration
B. National Center for Complementary and Alternative Medicine
C. International Association of Traditional Chinese Medicine

2. John Goodman, a frequent customer at your pharmacy, comes to the counter to pick up his monthly medications. He asks, “Would it be a bother to have you check out the rest of my items here as well?” Always one to help a customer, you tell him, “Of course, that’s fine!” You notice he has a botanic extract tincture that claims to help with heartburn. The ingredient list includes greater celandine (Chelidonium Majus). What organ dysfunction has been associated with this herb?
A. Liver injury
B. Kidney injury
C. Heart damage

3. A patient brings a brown bag of herbs and supplements for you to list on his profile. Which product may increase this patient’s risk for BOTH kidney and liver injury?
A. Pennyroyal essential oils
B. Germander weight loss tea
C. Impila fertility boost capsules

4. Mr. Goodman returns to your pharmacy. He explains he has been trying to live a healthier lifestyle, but has been feeling exceptionally tired after taking his as-needed alprazolam. Mr. Goodman goes on to tell you he’s added a new herbal supplement to his daily routine. You refer the patient to the pharmacist because you know and interaction between alprazolam and ______ could be causing the excessive drowsiness.
A. Echinacea
B. Garlic
C. Ginger

5. A customer at your pharmacy asks you for help in the herbal supplement aisle. She wants to take echinacea to boost her immune system, but she’d like more information about the manufacturer’s quality testing. You call the manufacturer for a certificate of analysis (CoA) only to be told they do not release them. Which of the following is most appropriate to tell this customer?
A. All herbal manufacturers are held to the same standards, so this brand is safe to use
B. This company likely has no quality assurance process; we should look for a better brand
C. This means the company uses an in-house laboratory for testing, so it is trustworthy

6. Your pharmacy is now selling a new herbal product. Curious about the contents, you decide to search for a certificate of analysis. On the bottle, you are looking for what three pieces of information?
A. product name, lot number, and expiration date
B. product name, manufacturer, and country of production
C. manufacturer, lot number, and date of production

8. Mrs. Jin is a longtime customer of your pharmacy who is on warfarin therapy for her atrial fibrillation. You ask to update her medication list in the system, including prescription, over-the-counter, and herbal supplements. Which of the following herbals would prompt you to refer Mrs. Jin to the pharmacist for counseling?
A. Chamomile
B. Kava kava
C. American ginseng

9. “These kids nowadays takin’ that codeine, and that awful dextromethorphan!” exclaimed Mr. O’Timer, “When I was a kid, and even now, all I ever took was licorice. My mom, bless her soul, would never let any poison enter MY body. To this day that’s all I use when I get a cold.” Trying to move him along before he inevitably tries to talk to you about politics, you stop as he mentions his busy day full of specialist appointments. Which specialist would be MOST LIKELY toned to know Mr. O’Timer is using licorice for his colds?
A. Dentist
B. Podiatrist
C. Cardiologist

Patient Safety: The Risk of Treatment: Antibiotic-Induced Adverse Events

After completing this application-based continuing education activity, pharmacists will be able to

· Describe mechanisms of action that cause antibiotic induced adverse effects

· Analyze risks and sequelae to determine adverse event or causative medication

· Recommend appropriate treatment for antibiotic induced adverse effect

· Discuss counseling points for outpatient antibiotic use

After completing this application-based continuing education activity, pharmacy technicians will be able to

· List adverse effects induced by antibiotics

·Recognize patients at risk of adverse effects

· Recall medications used to treat adverse effects

· Identify when to refer patient to pharmacist for recommendation or referral

When a patient is diagnosed with an infection, an antibiotic is usually the first line of treatment to cure the ailment. Antibiotics are effective treatments when patients have validated infections. Most often, treatment with antibiotics is benign. Typically, it does not pose a risk to patients, but antibiotics are associated with several risks to consider before initiating treatment. Risks of antibiotic use range from mild adverse effects of gastrointestinal upset and mild rash to life-threatening allergy development, toxic megacolon, and death. Recognizing and understanding the risks associated with antibiotic use is crucial in preventing severe patient complications.

INTRODUCTION

An injury or response that results in any harm to a patient after medication administration is an adverse drug reaction (ADR). Every medication can potentially cause ADRs, but antibiotics are notorious for causing several individual and class-wide type reactions. A 2017 study (N = 1488) showed that 20% of all inpatients who receive antibiotics will develop an ADR within 24 hours of therapy. That risk increases by 3% every ten days of therapy.¹ Education and recognition of ADRs from antibiotics are essential components in the campaign against antibiotic resistance. The Centers for Disease Control and Prevention (CDC) developed the Core Elements of Antibiotic Stewardship to optimize antibiotic use by decreasing unnecessary antibiotic prescribing and helping fight antibiotic resistance in different practice settings. One Core Element is education directed at prescribers, nurses, pharmacists, and patients about the adverse reactions associated with antibiotic use.²

Antibiotic Resistance

One of the most noxious antibiotic-induced ADRs is the development of antibiotic resistance. Antibiotic resistance is a global health threat to the world population and affects food security.³ Antibiotic resistance develops when a bacteria is no longer susceptible to a previously effective antibiotic, which can stem from unnecessary antibiotic use.¹ A 2011 study that surveyed American acute care hospitals found that almost half of all inpatients will receive at least one day of antibiotic therapy.⁴ A separate U.S. study found that one-third of all antibiotic treatment days are inappropriate.⁵

Antibiotic resistance kills at least 1.27 million people worldwide every year.⁶ The United States (U.S.) has reported more than 2.8 million antimicrobial-resistance infections yearly, with 35,000 deaths.⁷ Antimicrobial resistance can affect anyone at any age, at all different types of healthcare facilities, and in veterinary and agricultural industries.⁶ Antibiotic resistance prevents patients from using first or second-line therapy for indicated infections, making patients more susceptible to severe ADRs.

Antibiotic Allergies

Allergic reactions reportedly account for 20% of adverse drug events and are seen in about 8% of the population.⁸ Antibiotics are the most common medication reported as an allergy.⁹ Elderly and female patients are more likely to report antibiotic allergies.^9,10 Typically, antibiotic allergic reactions present as mild rash and hives but approximately 3% of the population’s health records documented past anaphylaxis.¹¹

In the 1960s, Robert Coombs and Philip Gell established a classification system for hypersensitivity reactions. Coombs is most notable for developing the Coombs test that detects anti-Rh antibodies on red blood cells in 1945.¹² Their classification system has four presentations of hypersensitivity reactions involving different immune mediators that develop into various manifestations. Table 1 summarizes the Coombs classification.

Table 1 - Classification of Allergic Reactions^13-15
Type	Description	Mechanism	Timing	Clinical features
I	IgE-mediated, immediate-type hypersensitivity	IgE serves to protect and eliminate parasitic infections. IgE antibodies form after exposure to allergens, such as food, drugs, or other environmental elements. Re-exposure triggers an immediate hypersensitivity reaction.	Minutes to hours after exposure	· Anaphylaxis · Angioedema · Bronchospasm · Hives · Hypotension · Asthma · Allergic rhinitis
II	Antibody-dependent cytotoxicity	The drug binds to the surface of the cell. Antibodies then bind to the cell surface and are targeted for clearance by macrophages. Usually involves IgG or IgM	Appear 5-8 days after exposure but can take longer	· Hemolytic anemia · Thrombocytopenia · Neutropenia
III	Immune complex disease	Soluble drug in bloodstream forms a complex with IgG or IgM. The immune complexes can activate complement and then deposits in various tissue like small blood vessels, joints, and renal glomeruli	One or more weeks to develop after drug exposure	· Serum sickness · Arthralgias · Acute glomerulonephritis · Vasculitis
IV	Cell-mediated hypersensitivity	Stimulation of T cells	At least 48-72 hours, but can take days to weeks following exposure	· Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN) · Drug rash with eosinophilia and systemic symptoms (DRESS) · Contact dermatitis

Antibiotic allergy reporting is essential to prevent patients from severe adverse effects, but it also comes with a risk. Prescribers overuse and overprescribe antibiotics. Overprescribing of antibiotics is associated with a higher incidence of new antibiotic allergies.⁹ In countries with low antibiotic usage, antibiotic allergies are less prevalent.⁹ Antibiotic overprescribing is especially notorious at urgent care facilities. A study showed that in patients presenting to urgent care for upper respiratory infections, healthcare providers prescribed antibiotics approximately twice as much as in emergency departments and nearly three times as much in primary care.¹⁶ This is concerning; nationwide, there are more than 10,000 urgent care facilities, and that number is growing.¹⁶

Inaccurate allergy documentation is another concern with antibiotic allergy reporting. Five percent to 15% of patients have documented penicillin allergies; however up to 90% of those patients can safely receive a penicillin antibiotic.^17,18 Antibiotic allergies prevent patients from receiving first-line therapy, which can increase health care costs, and increase the risk of treatment failures and adverse events.¹⁷ A study from 2003 showed that patients labeled with a penicillin allergy had a 63% greater cost for antibiotics than patients without a penicillin allergy.¹⁹

PAUSE AND PONDER: What are some individual antibiotics that make up penicillins and cephalosporins?

The best treatment for allergies is prevention. Before initiating any new antibiotic, the prescriber should obtain an allergy history. Pharmacists must review patients' profiles for allergies to beta-lactams and consider cross-reactivity. There is about a 2% risk of cross-sensitivity between penicillins and cephalosporins.¹⁷ Treatment for allergies depends on the type of reaction. Type I reactions are usually a medical emergency, and patients need immediate care. Antibiotic rechallenge is appropriate for patients with mild reactions like gastrointestinal distress or mild itching or rashes but should not occur for any patient who develops a severe reaction, like anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis, or hemolytic anemia.¹⁰ Reactions that occur need documentation with sufficient detail, including medication used and time to reaction.¹⁷

Antibiotic-Associated Diarrhea

A frequent adverse event associated with antibiotic use is diarrhea, defined as three or more loose stools in 24 hours.^20-22 Antibiotic-associated diarrhea reportedly occurs in 5% to 30% of patients while receiving or up to two months after receiving treatment.²³ Antibiotic-associated diarrhea’s clinical presentation can range from mild diarrhea to pseudomembranous colitis.^23,24 Essentially all antibiotics can cause diarrhea, especially those that cover anaerobic microorganisms (organisms that grow without oxygen) like amoxicillin/clavulante, cephalosporins, and clindamycin.^21-23

Antibiotic-associated diarrhea can occur from multiple mechanisms. First, antibiotics disrupt normal microflora, allowinge overgrowth of microorganisms known to cause diarrhea.²³ Clostridium difficile (C. diff), which will be discussed later, is the most common of those pathogens. Other pathogens are Salmonella, C. perfringens type A, Staphylococcus aureus, and Candida albicans.^20,24 Antibiotics can directly affect the intestinal mucosa, independent of any antibiotic activity. For example, erythromycin stimulates a receptor that increases contractions in the stomach and small intestines, and clavulanate can activate small bowel motility.^20,24 Last, antibiotics can decrease normal fecal flora that breakdown carbohydrates and bile acids in the colon. The increase of carbohydrates and bile acid causes an influx of water into the colon, causing osmotic diarrhea.^20,24

Treatment of antibiotic-associated diarrhea depends on its severity. Mild to moderate disease treatment should focus on rehydration, discontinuation of the provoking antibiotic, or changing to a lower-risk antibiotic like quinolones, sulfamethoxazole/trimethoprim, or aminoglycosides, if appropriate.^22,23 Clinicians should order C. diff testing in patients with severe or persistent disease or any microbes mentioned above.²³

Probiotics are an alternative method to decrease antibiotic-associated diarrhea, but mixed evidence surrounds their use. A 2021 meta-analysis reviewed 82 randomized controlled trials and found a statistically significant association between probiotic administration and the reduction of antibiotic-associated diarrhea.²⁵ The results are difficult to translate to a specific recommendation as the meta-analysis included many randomized controlled trials that did not document the exact probiotics used. In addition, the study excluded antibiotics that are more likely to cause diarrhea and specific subsets of patients like geriatrics.²⁵ Probiotic use is low risk for most patients, but immunocompromised patients should use caution when considering therapy.^26,27Probiotics are associated with rare secondary bacterial and fungal infections, which can be more prevalent in immunocompromised patients.^28-30 The most ideal way to prevent antibiotic-associated diarrhea is to limit antibiotic use.²

C. diff is a spore-forming bacteria that produces two separate exotoxins, A and B, that cause mucosal damage and inflammation.^22,23 Patients with C. diff infection (CDI) account for 10% to 25% of antibiotic-associated diarrhea cases, but CDI causes the majority of pseudomembranous colitis associated with antibiotic therapy.^23,24 Patients with CDI typically present with fever, lower abdominal pain, and cramping. CDI stool usually contains visible mucous and is foul-smelling.²² Significant risk factors include age older than 65, hospitalization, proton pump inhibitor use, and previous diagnosis of CDI.^22,24 Patients older than 60 have a much greater risk of developing CDI than patients aged 10 to 20 years.^24,31 Prescribers should consider C. diff testing after a patient has three or more unformed new or unexplained stools in 24 hours.¹²

Multiple diagnostic criteria confirm CDI. Lab results from CDI patients show elevated white blood cell count, decreased albumin, and fecal leukocytes.²⁴ Imaging with a CT scan can show inflammation and thickening of the colon, but it is not specific to CDI.²⁴ The Gold Standard testing for CDI is to test for toxins A and B with polymerase chain reaction (PCR) tests, but patients need to have unformed stool (bowel movement that is watery or soft) for this test. Patients with solid-formed stools do not have diarrhea and therefore do not have CDI, so testing is not warranted. Enzyme immunoassay (EIA) is another option that produces results much faster than the PCR test but has much lower sensitivity.^22,32

Providers should start treatment for C. diff after a positive test or before positive testing if a strong clinical suspicion exists.^24,32 Clinical guidelines do not recommend routine testing of C. diff in asymptomatic patients as C. diff colonization frequently occurs, especially in hospitalized patients and residents of long-term care facilities.³² Severity of disease, initial or recurrent occurrence, and other risk factors determine treatment. Disease severity can be non-severe, severe, or fulminant. In severe illness, the patient will have leukocytosis with a white blood cell count (WBC) of at least 15,000 cells/mL and a serum creatinine (Scr) level higher than 1.5 mg/dL. In non-severe disease, WBC and Scr levels are less than that of severe. Fulminant severity presents with hypotension or shock, ileus (an obstruction of the intestines), or megacolon (abnormal widening of the colon that is not caused by an obstruction).¹² Vancomycin and metronidazole have been the mainstay of treatment for more than 30 years until the development of newer medications. Fidaxomicin and bezlotuxumab are newer agents recently added to the Infectious Disease Society of America (IDSA) guidelines for CDI treatment.³³ Refer to 2021 IDSA guidelines for specific treatment recommendations.

Antibiotic-Induced Kidney Injury

Medications cause an estimated 20% to 40% of cases of acute kidney injury, with that estimation reaching almost 60% in the elderly population.^34,35 Antibiotics are a well-known cause of medication-induced renal dysfunction. Antimicrobials cause kidney dysfunction through tubular injury, severe tubular necrosis with cellular death, intratubular obstruction from crystal formation, and other mechanisms.³⁴ The direct cause is increased drug concentration, decreased excretion, and genetic differences predisposing some individuals to increased cell death or mitochondrial injury after exposure to certain antibiotics. In addition, patients with underlying kidney disease, acid-base disorders, and dehydration are at a greater risk of crystal formation with antibiotics that are insoluble in urine.^34,36 Most classes of antibiotics have varying degrees of risk for the development of renal dysfunction, but it is most commonly associated with aminoglycosides, beta-lactams, and vancomycin.^34,37

Renal dysfunction will develop in 10% to 25% of patients on aminoglycosides.^34,38 Symptoms of renal dysfunction develop five to seven days after initiation of therapy and will take up to 20 days for complete recovery after discontinuation of the aminoglycoside.^34,38 The risk for AKI increases in patients with longer therapy durations, exposure to concomitant nephrotoxins, and other comorbidities like chronic kidney disease.³⁸ Patients on aminoglycosides most commonly develop renal toxicity in the proximal tubule. Gentamicin has the highest potential to cause nephrotoxicity, followed by tobramycin and amikacin. Clinical practice has moved away from using neomycin systemically as it has an increased risk of causing nephrotoxicity, neurotoxicity, and ototoxicity.³⁴

Beta-lactams have a high risk of causing renal dysfunction, with carbapenems causing more renal toxicity than penicillins or cephalosporins.³⁴ Beta-lactams cause a wide range of renal toxicity, including acute glomerulonephritis, acute tubular necrosis, and acute interstitial nephritis.^34,39 Prolonged infusions of beta-lactams possess a similar risk of AKI compared to intermittent infusions.³⁹

Vancomycin’s incidence of nephrotoxicity is between 5% and 43%.^38,37,40 Vancomycin nephrotoxicity was initially associated with manufacturing impurities, but new manufacturing methods have eliminated this cause.^41-43 Onset occurs four to eight days after initiation of vancomycin and improves after discontinuation.^34,43 The overall pathophysiology of vancomycin-induced AKI is poorly understood as several mechanisms most likely contribute. Most patients who develop AKI on vancomycin do not undergo renal biopsies, and it is commonly prescribed with other nephrotoxic agents, which hinders a conclusive diagnosis.^34,38,43 Patients with pre-existing kidney disease, severe illness, a combination of nephrotoxic agents, obesity, and daily cumulative doses greater than four grams are at a higher risk of AKI.^34,41,44 Adjusting the vancomycin dose based on weight, levels, and renal function can help decrease the risk of kidney injury.³⁴ Pharmacists monitor vancomycin levels as trough and peaks which are low and high measurements of the actual medication in the patient.

Evidence of the risk of nephrotoxicity from the combination of vancomycin and piperacillin/tazobactam (VPT) has been conflicting. Previous evidence has shown VPT to carry a two to three-fold higher risk than vancomycin alone, but this is unclear due to piperacillin/tazobactam being a pseudo-nephrotoxin.^42,45 Prescribing information states that piperacillin/tazobactam can increase serum creatinine causing a pseudo-nephrotoxicity.⁴⁶ Most studies that reported increased risk of nephrotoxicity used increased creatinine as an indicator of acute kidney injury (AKI). ^45,47 A 2022 study looked at levels of cystatin C (a biomarker used to test kidney function) and found no significant change in its value for patients on VPT. Further, it also showed VPT combination did not lead to higher rates of dialysis or death.⁴⁸ Most recently in 2023, Chen et al. looked retrospectively at 35,644 patients receiving either VPT, vancomycin plus meropenem, or vancomycin plus cefepime. This study found that the combination of VPT has a greater risk of AKI, dialysis, and mortality in patients receiving treatment for greater than 48 hours.⁴⁹ At this time, available research on the VPT combination’s nephrotoxicity is conflicting. Clinicians should exercise caution when using VPT and consider other therapies in patients at high risk of renal dysfunction, especially if the combination will continue for longer durations.

Overall, antibiotics pose a significant risk to renal function, so the clinical team must assess risk factors of age and co-morbid conditions before initiating therapy.³⁴ A few ways to prevent the development of AKI are^34,38

dosages adjusted based on creatinine clearance and glomerular filtration rate (GFR)
changing the dose based on trough or random levels
adequate hydration, especially when using agents that form crystals in the urine
avoiding concomitant nephrotoxins (i.e., NSAIDs, contrast, etc.) and
regular monitoring of kidney function for long-term antibiotic use or when a patient has known risk factors for developing kidney dysfunction.

Clinicians must always practice good antimicrobial stewardship by prescribing shorter therapy courses to lower nephrotoxic agent exposure to the kidneys.³⁴

Sulfamethoxazole/Trimethoprim-Induced Hyperkalemia

The early 1980s through 1990s saw a significant rise worldwide of the human immunodeficiency virus (HIV) which also coincided with the first reported cases of hyperkalemia (high potassium levels) from sulfamethoxazole/trimethoprim (SMX/TMP). The CDC published a report in Morbidity and Mortality Weekly Report (MMWR) in June of 1981 describing the incidence of Pneumocystis carinii pneumonia (PCP; now known as Pneumocystis jirovecii), in five previously healthy young men.⁵⁰This CDC report documents the first known cases of HIV. Before the discovery of HIV, P. jirovecii was a disease associated with malnourished and immunocompromised patients. Premature and malnourished infants often contracted P. jirovecii during World War II, and patients with hematologic malignancies in later years.⁵¹ Dr. Walter Hughes, known for his research with P. jirovecii, first recommended SMX/TMP for prophylaxis in 1977 and then for treatment in 1989.^52-54 Emerging cases of hyperkalemia associated with SMX/TMP usage increased significantly at the start of the HIV epidemic as P. jirovecii treatment requires high doses and HIV patients are prone to the development of hyperkalemia.^55,56

SMX/TMP causes hyperkalemia because trimethoprim is structurally similar to the potassium-sparing diuretics amiloride and triamterene.^55,57 Trimethoprim blocks channels that excrete potassium into the urine, causing a potential 40% reduction of urinary potassium excretion.^58,59 Inhibition of urinary potassium excretion also decreases potassium in the urine.^55,58 Hyperkalemia will subside after discontinuation of trimethoprim.⁵⁸

Although SMX/TMP-induced hyperkalemia is low risk for most outpatients, it is essential to recognize risk factors and drug interactions because hyperkalemia is a medical emergency if untreated.⁶⁰Trimethoprim is excreted in the kidneys and will accumulate during acute and chronic kidney disease, which can increase the risk of hyperkalemia.⁶¹ Chronic kidney disease increases potassium levels, making it the most critical factor to consider when assessing risk for hyperkalemia.^57,62 Age greater than 65 and dose of greater than 20 mg/kg of trimethoprim for longer than a week also increases risk.^57,58

Risk assessment should include a review of any disease states or concomitant medications that could cause hyperkalemia (see Table 2). Studies have examined spironolactone’s effect when taken concurrently with SMX/TMP. A 2011 Canadian study examined patients receiving spironolactone and SMX/TMP prescriptions over 18 years. The study found that elderly patients treated with both medications had a 12-fold increased risk of hospital admission.⁶³ A 2015 Canadian study over 17 years looked at 206,319 patients to find an association between sudden death for patients taking spironolactone and antibiotics. Patients taking SMX/TMP were twice as likely to suffer from sudden death when compared to amoxicillin.⁵⁹

Table 2. Alternate Causes of Increased Risk of Hyperkalemia ^57,60,62
Disease States	Medications
Renal insufficiency	NSAIDs
AIDS patients	ACE/ARBs
Diabetes Mellitus	Direct Renin Inhibitors
Congestive Heart Failure	Beta-blockers
Metabolic Acidosis	Heparin
Congenital Adrenal Hyperplasia	Digoxin
Hypoaldosteronisim & Pseudohypoaldosteronism	Cyclosporine and tacrolimus
	Pentamidine
	Potassium-sparing Diuretics

Prevention of hyperkalemia from SMX/TMP should include decreasing the dose in patients with impaired renal function. SMX/TMP is contraindicated in patients with severe hepatic damage and severe renal disease if the patient does not have monitoring of renal function and electrolytes.^57,61 If hyperkalemia develops, prescribers should discontinue SMX/TMP and treat hyperkalemia following guideline recommendations.⁵⁸

Daptomycin-Induced Eosinophilic Pneumonia

The FDA approved daptomycin, a lipopeptide antibiotic, in 2003. Providers use it to treat complicated infections due to methicillin-resistant staph and vancomycin-resistant enterococci. Daptomycin has been an effective treatment alternative for patients who cannot use vancomycin due to intolerance or drug resistance.⁶⁴Daptomycin’s approved labeling lists eosinophilic pneumonia and myopathies as severe adverse events.

Eosinophilic pneumonia (EP) is a rare respiratory illness that can present with severe dyspnea, hypoxemia, and respiratory failure.^65-67 It is caused by eosinophil accumulation in the lungs as an acute or chronic process. Acute EP symptoms last less than one month and typically less than one week, while chronic presentation can take an average of five months before diagnosis.⁶⁸ Patients with acute EP present with a varying range in the presentation of symptoms. Some patients may have very mild symptoms and require no treatment, while some studies have shown much more severe manifestations, with more than 50% of patients requiring mechanical ventilation.^68,69 Patients typically present with a dry cough, chest pain, and fever.⁶⁸

EP develops when alveolar macrophages detect an antigen, which initiates an inflammatory process, eventually producing eosinophils and their subsequent migration to the lungs. Eosinophils are white blood cells that provide an essential defense against helminth parasites (worms). Reactions will develop in humans to presumably benign agents that incite a release of eosinophils.⁷⁰ In daptomycin-induced eosinophilic pneumonia, daptomycin is the inciting agent.

Accumulating eosinophils in the lungs or any tissue can cause significant damage.⁷¹ Eosinophils release toxic granule products like major basic protein and eosinophil peroxidase that can damage epithelial cells and nerves. They also release cytokines like transforming growth factors (TGF)-alpha and beta, which are associated with tissue remodeling and fibrosis.⁷¹ Alveolar macrophages, pulmonary endothelial cells, and airway smooth muscle cells also produce eotaxin, a potent chemoattractant of eosinophils.^65,72

EP’s primary causes are idiopathic.^68,72 Secondary reasons for EP are drugs or toxins and less commonly, parasitic or fungal infections.^68,72 The most frequently cited medications causing EP are daptomycin, mesalamine, sulfasalazine, and minocycline.⁶⁸ Daptomycin-induced EP was initially reported in 2007 after the drug’s approval.⁶⁵ Its pathophysiology is poorly understood. One proposed mechanism is that daptomycin may bind to human surfactant and accumulate in the alveolar space causing injury to the epithelium and subsequent eosinophil migration to the damaged tissue.^65,66,73 The second proposed mechanism is that daptomycin interacts with surfactant resulting in abnormal lipids. This contact induces an allergic reaction causing the release of several inflammatory markers and eventually shifts eosinophils into the respiratory tissue at least one week after the start of daptomycin therapy.^65,66,73

The Food and Drug Administration (FDA) has issued guidance for the diagnosis of daptomycin-induced EP with all of the following sequelae confirming a diagnosis of EP⁷⁴:

Concurrent exposure to daptomycin
Fever
Dyspnea with increasing oxygen demands requiring mechanical ventilation
New infiltrates on chest X-ray or CT
Bronchoalveolar lavage (BAL) with >25% eosinophils
Clinical improvement with daptomycin withdrawal

Risk factors have not been well established for daptomycin-induced EP. A 2016 study that reviewed 43 cases in systematic literature found that most patients were male (83%) and elderly (mean age of 65 years old). The same study found that dose or duration was not a risk factor.⁶⁶ A 2020 review looked specifically for risk with daptomycin and EP and found no association with age and sex. It also did not find an increased risk with high treatment doses. The study found, however, that around 30% of patients had diabetes or renal impairment.⁷⁵

Discontinuation of daptomycin should occur after a probable or definitive diagnosis of daptomycin-induced EP. Patients can experience respiratory failure from EP and may require oxygen supplementation or mechanical ventilation. Treatment can include a steroid taper starting with methylprednisolone and converting to prednisone over two to six weeks if appropriate.^65,66

Daptomycin-Induced Myopathy

Skeletal muscle effects are a rare but serious adverse event associated with daptomycin use. This adverse event presents as muscle weakness and pain, typically preceded by creatine phosphokinase (CPK) elevations.⁷⁶ In clinical trials, up to 6.7% of patients had elevated CPK levels, and daptomycin-associated myopathy occurred in 2% to 14% of patients.^77,78 During early clinical trials in the 1990s, researchers used 12-hour dosing intervals, but adverse skeletal muscle effects prohibited the trials from continuing.⁷⁹ Trials eventually restarted when once-daily dosing in dogs showed a lower incidence of CPK elevations.⁸⁰ Dosing frequency has a more direct relationship on skeletal muscle than peak plasma concentrations, making once daily daptomycin safer to administer than twice daily.⁸⁰

Skeletal muscle releases CPK from cells after various circumstances, including infections, intramuscular injections, and intense physical activity.⁸¹ The effect of daptomycin on skeletal muscle is thought to be from the drug's mechanism of action. Daptomycin works by breaking down the cell wall of bacteria, creating an opening, and causing a release of intracellular ions. In skeletal muscle, daptomycin also opens the cell wall and causes a release of intracellular CPK.⁸² Less frequent administration of daptomycin decreases the likelihood of CPK release as it allows skeletal muscle cells more time to repair.⁸²

Patients on concurrent statin therapy or who are obese (BMI >30) are at an increased risk of developing myopathies.⁷⁸ Daptomycin-induced myopathy is more likely to be seen with elevated daptomycin trough levels, but testing trough levels is expensive. Monitoring recommendations include weekly CPK levels to prevent skeletal muscle adverse events. More frequent monitoring should occur in patients with risk factors.^64,76 Holding statins when appropriate can help prevent adverse events during daptomycin administration.⁷⁸ Adverse skeletal muscle effects are reversible upon discontinuation of daptomycin.⁷⁶ Clinicians should discontinue daptomycin when CPK levels are more than 2000 U/L in asymptomatic patients or patients with CPK levels greater than 1000 U/L in symptomatic patients with no other reasoning for myopathies.⁶⁴

QT Prolongation

Medications are the most common cause of QT prolongation.⁸³ Medications can block specific outward potassium channels (IKr channels) in the heart, leading to QT prolongation. The slowing of outward potassium increases the plateau phase of the action potential, and electrocardiograms show a longer QT interval.⁸⁴ When potassium remains in the heart, the heart is kept at a positive charge that can prolong the repolarization phase. During this time, an ectopic beat generated by the heart can lead to Torsades de Pointe (TdP), a very dangerous and sometimes fatal arrhythmia.⁸⁵ Antibiotics like fluoroquinolones (FQ) and macrolides block IKr channels and can cause QT prolongation, which can potentially cause harm in patients with risk factors.

Macrolides and FQs are the most widely prescribed drugs in the inpatient and outpatient setting.⁸³ Levofloxacin and erythromycin have been cited most frequently for prescriptions in critical care and outpatient settings that cause QT prolongation.^86,87 A 2003 study found that a single dose of FQ administered to healthy patients can significantly prolong the QT interval when compared to placebo. The study demonstrated that moxifloxacin caused the most notable change, followed by levofloxacin and ciprofloxacin.⁸⁸ Ciprofloxacin and levofloxacin have more case reports of TdP than other fluoroquinolones but have a lower risk of QT prolongation. Their widespread use plays a more significant role in the incidence of TdP than their actual risk of developing QT prolongation.⁸³

A study reviewed the FDA Adverse Event Reporting System for patients who developed TdP. One-half of reports included macrolide use with no other concurrent QT-prolonging medications.⁸⁹ Of all the reports, 53% involved erythromycin use, while clarithromycin and azithromycin were 36% and 11%, respectively; further, in all of the reports that included erythromycin, 49% used intravenous (IV) erythromycin.⁸⁹ Of note, IV erythromycin use accounts for much less than other dosage forms with ointment at 66.1% of all prescriptions in 2020, oral dosages at 29.8% and all other forms including IV at 4.1%.⁹⁰

PAUSE AND PONDER: What medications can indirectly affect QT?

The risk of QT prolongation with antibiotics is difficult to assess as several factors can influence risk. Potassium channel blockade is concentration dependent; anything that increases the medication’s concentration will increase risk of QT prolongation.⁸³ Examples are rapid intravenous administration and impaired clearance through inhibition of hepatic metabolism.^83,91 Another important risk factor to consider is female sex, especially elderly females.^83,84,91,92 Female patients have consistently developed prolonged QT at a rate much higher than males and are more commonly prescribed medications that prolong the QT interval than males.⁸⁷ Older patients are more at risk for QT prolongation but are also more likely to have structural heart disease, drug interactions, and decreased drug clearance.⁹³ Risk assessments for QT prolongation should consider structural heart disease, subclinical long QT syndrome or genetic abnormalities, electrolyte abnormalities like hypokalemia and hypomagnesium, and patients with a family history of sudden death.^83,91,92 Pharmacists need to review concurrent medications for drug interactions that cause direct QT prolongation and medications that can affect QT indirectly, like diuretics, which can lead to electrolyte abnormalities.⁹²

For inpatients, baseline and subsequent electrocardiogram monitoring is an option for patients at high risk for QT prolongation, but it is too expensive to perform on every patient.⁹² Counseling for outpatients should include warning signs of arrhythmias like palpitations and near-syncope or syncope and other conditions that can affect potassium levels, like gastroenteritis or the addition of a diuretic.⁹² A risk assessment for QT prolongation is imperative for every patient started on a fluoroquinolone or macrolide.

Tendinopathy with Fluoroquinolones

In 1995, the FDA warned about the possibility of tendon rupture with fluoroquinolones.⁹⁴ Since then, several studies have looked at the risk of tendinopathies with FQ and found that they are associated with a two to four times increased risk of acute tendinopathy and tendon rupture. The risk is highest in the first month after drug exposure.^94,95 The Achilles tendon is most commonly involved as it is a weight-bearing tendon and more susceptible to injury, but any can occur in any tendon.^95-97

The mechanism of action of tendinopathy from fluoroquinolones needs to be better understood and may be multifactorial. One proposed mechanism is that fluoroquinolones increase substances known to cause tendons’ breakdown. In a study, matrix metalloproteinase (MMPs) increased after exposure to ciprofloxacin. MMPs cause collagen breakdown, which makes up 70% of tendons.⁹⁸ Another proposed mechanism is chelation. A study looked at connective tissue of magnesium-deficient dogs and found that the tissue had a similar damaged appearance to tissue treated with FQs. The study hypothesized that because FQs chelate with cations like magnesium, its effect on joints is similar to magnesium deficiency.⁹⁹

Patients are at a higher risk of developing tendinopathies with FQs if they are older than 60 years, transplant recipients, or on concurrent corticosteroid therapy.⁹⁴ Prescribers should avoid concurrent use of steroids and FQ as the risk of tendon rupture increases by 14-fold.⁹⁴ Treatment recommendations are discontinuing the offending agent and using supportive therapy like analgesia and physical therapy.⁹⁵ Approximately 90% of patients recover without surgery in one month, but 10% develop long-term adverse effects like difficulty walking, decreased mobility, and pain.⁹⁶

Cefepime-Induced Neurotoxicity

Cefepime is a 4^th generation cephalosporin available since 1997.¹⁰⁰ The package insert for cefepime warns against neurotoxicity, but it is a potential adverse effect with all beta-lactam antibiotics.¹⁰¹ Beta-lactams cause neurotoxicity because they antagonize the gamma-aminobutyric acid (GABA) receptor to varying degrees.¹⁰² Beta-lactams all have an affinity for GABA receptors because they are all structurally similar to GABA.^103,104 Cephalosporins, including cefepime, competitively inhibit the GABA receptor by binding directly to the receptor.^105,106

Cefepime-induced neurotoxicity (CIN) typically presents as encephalopathy, somnolence, agitation, confusion, and disorientation, while aphasia and hallucinations are less common.^107-109 Patients occasionally will develop convulsions or non-convulsive status epilepticus.¹¹⁰

The most significant risk factor for CIN is renal dysfunction.^100,104,108 When a patient with poor renal function receives cefepime, a higher concentration of unbound medication stays within the cerebrospinal fluid, causing symptoms when it enters the central nervous system.¹⁰⁸ A study of 42 patients with CIN found that 93% of patients with neurotoxicity had abnormal renal function, and 76% of the studied patients had their cefepime dose adjusted appropriately.¹⁰² A study has shown that CIN occurred despite dose reductions and even in dosages of 500 mg daily in patients with ESRD.¹¹¹

In addition to renal dysfunction, several other risk factors for CIN need review. Overdose or use of excessive dosages puts patients at risk for CIN, and it is much more likely to be seen in patients without appropriate dose adjustments.^108,109 Drug monitoring sometimes includes measurement of the medication in the blood called a peak (highest) and trough (lowest) levels. A study has associated CIN with high trough levels. The study showed neurotoxicity did not occur at troughs of less than 7.7 mg/L, while it always manifested at troughs at or exceeding 38.1 mg/L. The study’s author has suggested a trough of 7.5mg/L as a potential target.¹¹² Patients 65 and older are at risk because of pharmacokinetic changes.^100,113 Although age is a significant risk factor, CIN will occur in 25% of patients younger than 65.¹⁰⁰ Last, patients with underlying brain diseases like cerebrovascular accident, Korsakoff’s syndrome, small-vessel disease, Alzheimer’s disease, benign brain tumor, malignancy, or previous seizures are at risk for CIN.^108,114

Prescribers should discontinue cefepime in patients who develop suspected CIN.^100,108 It typically takes two to three days to resolve symptoms.^100,108 Providers can initiate dialysis in patients experiencing severe symptoms as it can rapidly decrease the concentration of cefepime.¹¹⁴ Medications that stimulate the GABA receptor, like benzodiazepines or barbiturates, are more effective than phenytoin in patients who develop seizures.¹⁰⁴ Last, switching antibiotics can sometimes resolve symptoms, but symptom prolongation can occur with other beta-lactams like piperacillin and meropenem. Consider alternative antibiotic classes in appropriate patients.¹⁰⁸

Linezolid-Induced Thrombocytopenia

Linezolid belongs to a class of medications called oxazolidinones. The discovery and investigation of oxazolidinones occurred in the late 1980s, but development did not continue due to severe adverse events in animals.¹¹⁵ In the 1990s, scientists from the Pharmaca Corporation derived linezolid from the oxazolidinones class, and the FDA approved its use in April 2000 after clinical safety testing.¹¹⁶ Linezolid has a considerable advantage for treating severe gram-positive infections as it is available intravenous (IV) but also has 100% oral bioavailability.¹¹⁷ Another advantage of linezolid is it’s relatively safe to use, with only 0.4% of patients experiencing severe adverse effects in phase 3 trials.¹¹⁵ Several case reports of adults experiencing varying types of myelosuppression, like anemia or pancytopenia, emerged following linezolid’s clinical approval, but thrombocytopenia (low platelets) is the most prevalent.¹¹⁵

Linezolid-induced thrombocytopenia (TP) takes approximately seven to 14 days before onset.^115,118 Reports of TP differ depending on geographical location or definition used.^118-120 TP typically takes around 14 days to develop because the platelet has a seven to ten day life cycle.¹¹⁵ Although studies have proposed several mechanisms, a definitive cause has yet to be established.¹²⁰

Patients with the following risk factors need monitoring for the development of thrombocytopenia^{115,118,121,120}:

Prolonged treatment course greater than 14 days
Underlying disease with a predisposition to hematologic abnormalities
Renal dysfunction, CrCl less than 30 ml/min, and dialysis. Linezolid is not primarily cleared renally but metabolized into two compounds. These compounds are renally eliminated and can accumulate in patients with renal dysfunction and may play a role in the development of thrombocytopenia
Chronic liver failure
History of vancomycin use
Low baseline platelet level of less than 200
Low body weight–Linezolid dosing does not change for adults nor require renal or hepatic impairment adjustment. When body weight decreases and total mg/kg of linezolid increases, the risk of thrombocytopenia increases. A study found that daily mg/kg doses between 22-27 (body weight between 55-70 kg) had a 48% chance of developing thrombocytopenia versus 72% in dosages greater than 27 mg/kg (body weight less than or equal to 45kg).

Discontinuation of linezolid should occur for patients who develop thrombocytopenia or any myeloid cell abnormality while on therapy.¹¹⁵ Myelosuppression is reversible after discontinuation of linezolid. Patients actively receiving therapy should have weekly monitoring of complete blood count and renal function monitoring.¹²¹ Monitoring is essential in patients receiving treatment for longer than 14 days, have pre-existing myelosuppression, take concurrent medications that cause myelosuppression, or have received prior antibiotic therapy from a chronic infection.¹¹⁷

Reporting ADRs

Identifying ADRs as they occur is vital to comprehensive patient care, but reporting ADRs is equally essential. The FDA established MedWatch in 1993 as a tool for healthcare providers and consumers to voluntarily report ADRs. ADRs can be reported through MedWatch or directly to drug manufacturers, who then are required to report ADRs to the FDA. The FDA uses the reported ADRs to make up the Adverse Event Reporting System (AERS), a postmarketing surveillance database. The information entered into AERS helps identify trends that are useful in determining causes and preventing prospective events.^122,123

PAUSE AND PONDER: Why is it important to include so much information when reporting ADRs?

The FDA defines a serious Adverse Drug Event (ADE) as fatal, life-threatening, incites hospitalization or prolongation of existing admission, causes significant disability, or congenital disability or anomaly to the patient.¹²⁴ The FDA asks healthcare providers and manufacturers to report all serious ADEs. Healthcare providers, including pharmacists, should also report any non-serious unexpected ADEs. These reports are helpful, even if the reaction is not directly related to the drug, as the reports may help discover unidentified ADEs. Healthcare providers should submit as much information as possible that is relevant to the ADE.¹²² Table 3 includes essential information to include in ADE reporting.

Table 3. Key-Inclusions for High-Quality ADE Report¹²⁵

· Clear description of event or outcome, include time to onset of signs and symptoms;

· Suspected and concurrent medications details: dose, lot number, schedule, dates, duration (Include non-prescription medications, dietary supplements, and any recently discontinued medications);

· Patient characteristics, including demographics (e.g., age, sex, race), baseline medical condition prior to treatment, co-morbid conditions, medication allergies, relevant family history, other risk factors;

· Documentation of diagnosis, including methods of making diagnosis;

· Clinical course of event and outcome (e.g., death, hospitalization, treatment);

· Relevant objective information (e.g., laboratory data) at baseline, during therapy, and after therapy;

· Response to discontinuation of therapy and re-initiation if available;

· Any other relevant information.

Conclusion

This continuing education activity discusses only a fraction of commonly experienced adverse drug reactions associated with antibiotics. It is not an exhaustive list, but it provides valuable guidance for healthcare providers for antibiotics with established reactions and serves as a reminder to report any serious or atypical reactions that may occur while using new antibiotics.

Antibiotic-associated adverse drug reactions are a significant concern in healthcare. These reactions occur when antibiotics lead to unintended harmful effects, such as allergic reactions, organ damage, or antibiotic resistance. Inappropriate use or overuse of antibiotics increases risk of adverse reactions. Decreased renal and hepatic function, elderly patients, and drug interactions are common risks of developing ADRs in antibiotics. Recognizing risks and following recommended monitoring can help prevent ADRs from occurring. Anyone directly involved in direct patient care should report suspected ADRs and educate patients on the impact of these events to ensure the safe and effective use of antibiotics.

Title: Patient Safety: The Risk of Treatment: Antibiotic induced adverse events
Objectives
Pharmacists
• DESCRIBE mechanisms of action that can cause antibiotic induced adverse effects
• ANALYZE risks and sequelae to determine adverse event or causative medication
• RECOMMEND appropriate treatment for antibiotic induced adverse effect
• DISCUSS counseling points for outpatient antibiotic use

1. A patient recently filled penicillin for treatment of strep throat. She returns back to the pharmacy the following day with a prescription for a new antibiotic and an epi-pen. She describes having a sudden reaction of hives, shortness of breath and facial swelling after a dose of penicillin and having to go to the hospital for treatment. What type of reaction did the patient have?
A. Type I
B. Type II
C. Type III

2. What type of reaction is appropriate to consider re-challenging an antibiotic if a patient develops an allergy?
A. Steven Johnsons Syndrome
B. Mild Itching
C. Anaphylaxis

3. A 40-year-old female with history of kidney transplant on immunosuppressants was started on antibiotics for pneumonia. The patient is afebrile has developed mild to moderate diarrhea from antibiotics and the medical team is looking for recommendations. What is appropriate treatment for this patient?
A. Probiotics
B. Start treatment for C diff infection
C. Rehydration

4. Sara is an 80-year-old female who has recently been diagnosed with a UTI and started on sulfamethoxazole/trimethoprim. She also has heart failure, DVT and COPD and also uses spironolactone, apixiban and albuterol nebulizer. What comorbid condition and medication increase her risk of hyperkalemia from SMX/TMP?
A. Heart failure patient on spironolactone
B. DVT on apixiban
C. Asthma exacerbation on albuterol nebulizers

5. Paul is a 75-year-old male who was admitted to the hospital for septic arthritis and started on vancomycin. After three doses of vancomycin, Paul develops an allergic reaction and he is switched to daptomycin. Five days later, Paul starts coughing, develops a fever, and his oxygenation levels drop. The attending physician orders a BAL; it shows an increase of eosinophils. He is diagnosed with eosinophilic pneumonia from daptomycin. What is an appropriate treatment recommendation?
A. An alternative antibiotic to treat the pneumonia
B. Albuterol to increase oxygenation levels
C. Discontinuation of daptomycin and start steroids

6. At a community pharmacy, a patient asks what you recommend for pain medication for muscle aches. Upon further questioning, you find that the patient has been on outpatient infusions of daptomycin for a diabetic foot infection for a few weeks. The patient is obese and says he thinks the muscle aches must just be from getting old. What is this patient most likely experiencing?
A. Daptomycin induced myopathy
B. Diabetes induced neuropathy
C. Muscle aches from infection

7. What laboratory value increases when patients develop daptomycin-related myopathy?
A. Scr
B. CPK
C. Eosinophils

8. What medication causes an indirect risk for this patient to develop QT prolongation?
A. Furosemide
B. Acetaminophen
C. Amiodarone

9. You have phoned Cecelia’s provider and determined he wants to continue ciprofloxacin despite the risk of QT prolongation. What is appropriate to include when counseling?
A. Patient needs daily EKG monitoring while taking ciprofloxacin and can use her iWatch to do the monitoring
B. Any new diarrhea does not need to be reported to the provider as its expected with antibiotics
C. Patient should be aware of warning signs of arrhythmias like palpitations and near-syncope or syncope
.
10. What medication should be avoided concurrently with fluoroquinolones because it increases the risk of tendon rupture?
A. Magnesium
B. Ibuprofen
C. Prednisone
.
11. Why are beta-lactams associated with causing neurotoxicity?
A. They deplete the availability of GABA
B. They increase the production of GABA
C. They are structurally similar to GABA
.
12. Paul is a 41 YO male with a history of end stage renal disease admitted to the hospital for pneumonia. He is initially started on dose adjusted cefepime and vancomycin and starts to improve. Three days after initial therapy cultures come back growing pseudomonas sensitive to cefepime, ciprofloxacin, and piperacillin/tazobactam but he has altered mental status and is very somnolent. What is your recommendation for treatment?
A. Discontinue cefepime and switch to non-beta lactam antibiotic
B. Discontinue cefepime and switch to alternative beta-lactam antibiotic
C. Continue cefepime and discontinue vancomycin

13. Patti comes to your pharmacy with a prescription for a brand new antibiotic that has recently been approved for UTI. After discussing expected adverse effects, what is also important to include about adverse effects?
A. She should ignore any other adverse effects she experiences as they have not been reported so they could not possibly be from the new antibiotic
B. She should report any undocumented adverse effects to her prescriber or pharmacist as it can help discover unidentified adverse drug reactions
C. She should post about any new adverse effects on her social media because all drug companies use artificial intelligence to screen for new adverse effects

Title: Patient Safety: The Risk of Treatment: Antibiotic induced adverse events
Objectives
Technicians
• LIST adverse effects induced by antibiotics #6
• RECOGNIZE patients at risk of adverse effects #3
• RECALL medications used to treat adverse effects #2
• IDENTIFY when to refer patient to pharmacist for recommendation or referral #2

1. What is the most common pathogen known to cause antibiotic-associated diarrhea?
A. Clostridium difficile
B. Staphylococcus aureus
C. Candida albicans
.
2. A patient comes to the pharmacy to drop off a new prescription for cephalexin. When reviewing the profile, you notice an allergy for amoxicillin. There is no information about what the reaction is to amoxicillin. What is the appropriate action?
A. Ignore the allergy and fill the prescription, the risk of cross-reactivity is low.
B. Instruct the patient to contact the prescriber for a different antibiotic
C. Alert the pharmacist and let them determine the appropriate actions
.
3. Which of the following conditions can be treated with fidaxomicin?
A. C difficile infection
B. Antibiotic allergies
C. Kidney dysfunction
.
4. Which antibiotic is more likely to cause kidney injury
A. Clindamycin
B. Metronidazole
C. Gentamicin
.
5. What electrolyte does sulfamethoxazole/trimethoprim increase?
A. Magnesium
B. Potassium
C. Sodium

6. What medication can be used to treat daptomycin-induced eosinophilic pneumonia?
A. Methylphenidate
B. Methylprednisolone
C. Methylnaltrexone
.
7. What patient is at increased risk for daptomycin induced myopathy?
A. BMI <18.5 B. BMI 18.5-30 C. BMI >30
.
8. Macrolides and quinolones cause a certain cardiac side effect. What is it?
A. Congestive heart failure
B. Endocarditis
C. QT prolongation
.
9. What tendon is most often associated with tendon rupture from fluoroquinolones?
A. Achilles Tendon
B. Quadriceps Tendon
C. Biceps Tendon
.
10. Which antibiotic has been associated with neurotoxicity as an adverse effect?
A. Clindamycin
B. Cefepime
C. Clarithromycin

11. What organ dysfunction makes patients more at risk for adverse drug reactions associated with cefepime?
A. Kidney
B. Liver
C. Heart
.
12. Which of the following increases patients’ risks for linezolid induced thrombocytopenia?
A. Short therapy course
B. Obesity
C. Low baseline platelets
.
13. A patient comes to the pharmacy stating that ever since he started taking a new antibiotic, sarecycline, he has lost his appetite and found it difficult to eat. The patient tried to research if the medication causes that reaction but could not find any information. What should you do?
A. Refer the patient to the pharmacist; this reaction may need to be reported as a potential adverse drug event to the drug manufacturer and FDA
B. Tell the patient to not worry as if he cannot find any information about it, this adverse effect is not related to the medication
C. Instruct the patient to not trust information from the Internet because in most cases, an unreliable source posted the information

1. Tamma PD, Avdic E, Li DX, Dzintars K, Cosgrove SE. Association of adverse events with antibiotic use in hospitalized patients. JAMA Internal Medicine. 2017;177(9):1308. doi:10.1001/jamainternmed.2017.1938
2. Core Elements of Hospital Antibiotic Stewardship Programs. Centers for Disease Control and Prevention. Published April 28, 2021. Accessed January 3, 2023. https://www.cdc.gov/antibiotic-use/core-elements/hospital.html#anchor_1617121904865
3. World Health Organization. Antibiotic Resistance. World Health Organization. Published July 31, 2020. Accessed January 9, 2023https://www.who.int/news-room/fact-sheets/detail/antibiotic-resistance
4. Magill SS, Edwards JR, Beldavs ZG, et al. Prevalence of antimicrobial use in US acute care hospitals, May-September 2011. JAMA. 2014;312(14):1438-1446. doi:10.1001/jama.2014.12923
5. Hecker MT, Aron DC, Patel NP, Lehmann MK, Donskey CJ. Unnecessary use of antimicrobials in hospitalized patients: current patterns of misuse with an emphasis on the antianaerobic spectrum of activity. Arch Intern Med. 2003;163(8):972-978. doi:10.1001/archinte.163.8.972
6. Antibiotic / antimicrobial resistance. Centers for Disease Control and Prevention. Published December 17, 2021. Accessed January 9, 2023. https://www.cdc.gov/drugresistance/index.html.
7. Antibiotic Resistance Threats in the United States, 2019. Centers for Disease Control and Prevention. Accessed May 16, 2023. https://stacks.cdc.gov/view/cdc/82532
8. Blumenthal KG, Peter JG, Trubiano JA, Phillips EJ. Antibiotic allergy. The Lancet. 2019;393(10167):183-198. doi:10.1016/s0140-6736(18)32218-9
9. Macy E. Addressing the epidemic of antibiotic “allergy” over-diagnosis. Annals of Allergy, Asthma & Immunology. 2020;124(6):550-557. doi:10.1016/j.anai.2019.12.016
10. Macy E, Ho NJ. Multiple drug intolerance syndrome: prevalence, clinical characteristics, and management. Ann Allergy Asthma Immunol. 2012;108(2):88-93. doi:10.1016/j.anai.2011.11.006
11. Goss FR, Lai KH, Topaz M, et al. A value set for documenting adverse reactions in electronic health records. J Am Med Inform Assoc. 2018;25(6):661-669. doi:10.1093/jamia/ocx139
12. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48. doi:10.1093/cid/cix1085
13. Uzzaman A, Cho SH. Chapter 28: Classification of hypersensitivity reactions. Allergy Asthma Proc. 2012;33 Suppl 1:96-99. doi:10.2500/aap.2012.33.3561
14. Weiss ME, Adkinson NF. Immediate hypersensitivity reactions to penicillin and related antibiotics. Clin Allergy. 1988;18(6):515-540. doi:10.1111/j.1365-2222.1988.tb02904.x
15. Pichler, WJ. Drug hypersensitivity: Classification and Clinical features. In: Post T, ed. UpToDate. Waltham,Mass.:UpToDate; 2023. www.uptodate.com. Accessed June 21, 2023
16. Palms DL, Hicks LA, Bartoces M, et al. Comparison of Antibiotic Prescribing in Retail Clinics, Urgent Care Centers, Emergency Departments, and Traditional Ambulatory Care Settings in the United States. JAMA Intern Med. 2018;178(9):1267-1269. doi:10.1001/jamainternmed.2018.1632
17. Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of Penicillin allergy. JAMA. 2019;321(2):188. doi:10.1001/jama.2018.19283
18. Joint Task Force on Practice Parameters; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology; Joint Council of Allergy, Asthma and Immunology. Drug allergy: an updated practice parameter. Ann Allergy Asthma Immunol. 2010;105(4):259-273. doi:10.1016/j.anai.2010.08.002
19. Sade K, Holtzer I, Levo Y, Kivity S. The economic burden of antibiotic treatment of penicillin-allergic patients in internal medicine wards of a general tertiary care hospital. Clin Exp Allergy. 2003;33(4):501-506. doi:10.1046/j.1365-2222.2003.01638.x
20. Högenauer C, Hammer HF, Krejs GJ, Reisinger EC. Mechanisms and management of antibiotic-associated diarrhea. Clin Infect Dis. 1998;27(4):702-710. doi:10.1086/514958
21. Wiström J, Norrby SR, Myhre EB, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother. 2001;47(1):43-50. doi:10.1093/jac/47.1.43
22. Giannelli FR. Antibiotic-associated diarrhea. JAAPA. 2017;30(10):46-47. doi:10.1097/01.JAA.0000524721.01579.c9
23. Barbut F, Meynard JL. Managing antibiotic associated diarrhoea. BMJ. 2002;324(7350):1345-1346. doi:10.1136/bmj.324.7350.1345
24. Bartlett JG. Clinical practice. Antibiotic-associated diarrhea. N Engl J Med. 2002;346(5):334-339. doi:10.1056/NEJMcp011603
25. Hempel S, Newberry SJ, Maher AR, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea: a systematic review and meta-analysis. JAMA. 2012;307(18):1959-1969. doi:10.1001/jama.2012.3507
26. Lactobacillus: Drug information. In: Post T, ed. UpToDate. Waltham,Mass.:UpToDate; 2023. www.uptodate.com. Accessed January 19, 2023
27. Saccharomyces boulardii: Drug information. In: Post T, ed. UpToDate. Waltham,Mass.:UpToDate; 2023. www.uptodate.com. Accessed January 19, 2023
28. Fredenucci I, Chomarat M, Boucaud C, Flandrois JP. Saccharomyces boulardii fungemia in a patient receiving Ultra-levure therapy. Clin Infect Dis. 1998;27(1):222-223. doi:10.1086/517685
29. Riquelme AJ, Calvo MA, Guzmán AM, et al. Saccharomyces cerevisiae fungemia after Saccharomyces boulardii treatment in immunocompromised patients. J Clin Gastroenterol. 2003;36(1):41-43. doi:10.1097/00004836-200301000-00013
30. Land MH, Rouster-Stevens K, Woods CR, Cannon ML, Cnota J, Shetty AK. Lactobacillus sepsis associated with probiotic therapy. Pediatrics. 2005;115(1):178-181. doi:10.1542/peds.2004-2137
31. Karlström O, Fryklund B, Tullus K, Burman LG. A prospective nationwide study of Clostridium difficile-associated diarrhea in Sweden. The Swedish C. difficile Study Group. Clin Infect Dis. 1998;26(1):141-145. doi:10.1086/516277
32. Kelly CR, Fischer M, Allegretti JR, et al. ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections [published correction appears in Am J Gastroenterol. 2022 Feb 1;117(2):358]. Am J Gastroenterol. 2021;116(6):1124-1147. doi:10.14309/ajg.0000000000001278
33. Johnson S, Lavergne V, Skinner AM, et al. Clinical Practice Guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 Focused Update Guidelines on Management of Clostridioides difficile Infection in Adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549
34. Morales-Alvarez MC. Nephrotoxicity of Antimicrobials and Antibiotics. Adv Chronic Kidney Dis. 2020;27(1):31-37. doi:10.1053/j.ackd.2019.08.001
35. Kim SY, Moon A. Drug-induced nephrotoxicity and its biomarkers. Biomol Ther (Seoul). 2012;20(3):268-272. doi:10.4062/biomolther.2012.20.3.268
36. Berns JS, Cohen RM, Stumacher RJ, Rudnick MR. Renal aspects of therapy for human immunodeficiency virus and associated opportunistic infections. J Am Soc Nephrol. 1991;1(9):1061-1080. doi:10.1681/ASN.V191061
37. Cosgrove SE, Vigliani GA, Fowler VG Jr, et al. Initial low-dose gentamicin for Staphylococcus aureus bacteremia and endocarditis is nephrotoxic. Clin Infect Dis. 2009;48(6):713-721. doi:10.1086/597031
38. Perazella MA, Rosner MH. Drug-Induced Acute Kidney Injury. Clin J Am Soc Nephrol. 2022;17(8):1220-1233. doi:10.2215/CJN.11290821
39. Cotner SE, Rutter WC, Burgess DR, Wallace KL, Martin CA, Burgess DS. Influence of β-Lactam Infusion Strategy on Acute Kidney Injury. Antimicrob Agents Chemother. 2017;61(10):e00871-17. Published 2017 Sep 22. doi:10.1128/AAC.00871-17
40. van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother. 2013;57(2):734-744. doi:10.1128/AAC.01568-12
41. Nolin TD. Vancomycin and the Risk of AKI: Now Clearer than Mississippi Mud. Clin J Am Soc Nephrol. 2016;11(12):2101-2103. doi:10.2215/CJN.11011016
42. Blair M, Côté JM, Cotter A, Lynch B, Redahan L, Murray PT. Nephrotoxicity from Vancomycin Combined with Piperacillin-Tazobactam: A Comprehensive Review. Am J Nephrol. 2021;52(2):85-97. doi:10.1159/000513742
43. Filippone EJ, Kraft WK, Farber JL. The Nephrotoxicity of Vancomycin. Clin Pharmacol Ther. 2017;102(3):459-469. doi:10.1002/cpt.726
44. Bamgbola O. Review of vancomycin-induced renal toxicity: an update. Ther Adv Endocrinol Metab. 2016;7(3):136-147. doi:10.1177/2042018816638223
45. Luther MK, Timbrook TT, Caffrey AR, Dosa D, Lodise TP, LaPlante KL. Vancomycin Plus Piperacillin-Tazobactam and Acute Kidney Injury in Adults: A Systematic Review and Meta-Analysis. Crit Care Med. 2018;46(1):12-20. doi:10.1097/CCM.0000000000002769
46. Zosyn® [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017
47. Rutter WC, Hall RG, Burgess DS. Impact of total body weight on rate of acute kidney injury in patients treated with piperacillin-tazobactam and vancomycin. Am J Health Syst Pharm. 2019;76(16):1211-1217. doi:10.1093/ajhp/zxz120
48. Miano TA, Hennessy S, Yang W, et al. Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study. Intensive Care Med. 2022;48(9):1144-1155. doi:10.1007/s00134-022-06811-0
49. Chen AY, Deng CY, Calvachi-Prieto P, et al. A Large-Scale Multicenter Retrospective Study on Nephrotoxicity Associated With Empiric Broad-Spectrum Antibiotics in Critically Ill Patients. Chest. 2023;164(2):355-368. doi:10.1016/j.chest.2023.03.046
50. Pneumocystis Pneumonia. Morbidity and Mortality Weekly Report. Published June 5, 1981. Accessed June 22, 2023. https://www.cdc.gov/mmwr/preview/mmwrhtml/june_5.htm
51. Thomas CF, Limper AH. Epidemiology, clinical manifestations, and diagnosis of Pneumocystis pneumonia in patients without HIV. In: Post T, ed. Waltham,Mass.:UpToDate; 2023. www.uptodate.com. Accessed June 24, 2023.
52. Hughes WT, Kuhn S, Chaudhary S, Feldman S, Verzosa M, Aur RJ, Pratt C, George SL. Successful chemoprophylaxis for Pneumocystis carinii pneumonitis. N Engl J Med. 1977 Dec 29;297(26):1419-26. doi: 10.1056/NEJM197712292972602. PMID: 412099.
53. Hughes WT. Treatment and prophylaxis for Pneumocystis carinii pneumonia. Parasitol Today. 1987;3(11 ):332-335. doi:10.1016/0169-4758(87)90116-5
54. Ligon BL. Biography: Walter T. Hughes, MD: Pioneer and leader in the battle against pneumocystis carinii pneumonia. Semin Pediatr Infect Dis. 2001;12(4):323-333. https://doi.org/10.1053/spid.2001.28615.
55. Choi MJ, Fernandez PC, Patnaik A, et al. Brief report: trimethoprim-induced hyperkalemia in a patient with AIDS. N Engl J Med. 1993;328(10):703-706. doi:10.1056/NEJM199303113281006
56. Haseeb A, Abourehab MAS, Almalki WA, et al. Trimethoprim-Sulfamethoxazole (Bactrim) Dose Optimization in Pneumocystis jirovecii Pneumonia (PCP) Management: A Systematic Review. Int J Environ Res Public Health. 2022;19(5):2833. Published 2022 Feb 28. doi:10.3390/ijerph19052833
57. Smith CA. Trimethoprim-Sulfamethoxazole and Hyperkalemia. Nephrol Nurs J. 2021;48(2):177-180.
58. Eiam-Ong S, Kurtzman NA, Sabatini S. Studies on the mechanism of trimethoprim-induced hyperkalemia. Kidney Int. 1996;49(5):1372-1378. doi:10.1038/ki.1996.193
59. Antoniou T, Hollands S, Macdonald EM, et al. Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone. CMAJ. 2015;187(4):E138-E143. doi:10.1503/cmaj.140816
60. Alappan R, Buller GK, Perazella MA. Trimethoprim-sulfamethoxazole therapy in outpatients: is hyperkalemia a significant problem?. Am J Nephrol. 1999;19(3):389-394. doi:10.1159/000013483
61. Trimethoprim-sulfamethoxazole: Drug information. In: Post T, ed. UpToDate. Waltham,Mass.:UpToDate; 2023. www.uptodate.com. Accessed July 10, 2023
62. Kovesdy CP. Updates in hyperkalemia: Outcomes and therapeutic strategies. Rev Endocr Metab Disord. 2017;18(1):41-47. doi:10.1007/s11154-016-9384-x
63. Antoniou T, Gomes T, Mamdani MM, et al. Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study. BMJ. 2011;343:d5228. Published 2011 Sep 12. doi:10.1136/bmj.d5228
64. Daptomycin [package insert]. Whitehouse Station, NJ:Merck & Co LLC; 2017.
65. Uppal P, LaPlante KL, Gaitanis MM, Jankowich MD, Ward KE. Daptomycin-induced eosinophilic pneumonia - a systematic review. Antimicrob Resist Infect Control. 2016;5:55. Published 2016 Dec 12. doi:10.1186/s13756-016-0158-8
66. Hirai J, Hagihara M, Haranaga S, et al. Eosinophilic pneumonia caused by daptomycin: Six cases from two institutions and a review of the literature. J Infect Chemother. 2017;23(4):245-249. doi:10.1016/j.jiac.2016.09.001
67. Hayes D Jr, Anstead MI, Kuhn RJ. Eosinophilic pneumonia induced by daptomycin. J Infect. 2007;54(4):e211-e213. doi:10.1016/j.jinf.2006.11.006
68. Bartal C, Sagy I, Barski L. Drug-induced eosinophilic pneumonia: A review of 196 case reports. Medicine (Baltimore). 2018;97(4):e9688. doi:10.1097/MD.0000000000009688
69. Jhun BW, Kim SJ, Kim K, Lee JE. Outcomes of rapid corticosteroid tapering in acute eosinophilic pneumonia patients with initial eosinophilia. Respirology. 2015;20(8):1241-1247. doi:10.1111/resp.12639
70. Conroy DM, Williams TJ. Eotaxin and the attraction of eosinophils to the asthmatic lung. Respir Res. 2001;2(3):150-156. doi:10.1186/rr52
71. Weller PF, Klion AD. Eosinophil biology and causes of eosinophilia. In: Post T, ed. UpToDate. Waltham,Mass.:UpToDate; 2023. www.uptodate.com. Accessed February 19, 2023.
72. Miller BA, Gray A, Leblanc TW, Sexton DJ, Martin AR, Slama TG. Acute eosinophilic pneumonia secondary to daptomycin: a report of three cases. Clin Infect Dis. 2010;50(11):e63-e68. doi:10.1086/652656
73. Cobb E, Kimbrough RC, Nugent KM, Phy MP. Organizing pneumonia and pulmonary eosinophilic infiltration associated with daptomycin. Ann Pharmacother. 2007;41(4):696-701. doi:10.1345/aph.1H372
74. FDA Drug Safety Communication: Eosinophilic pneumonia associated with the use of Cubicin (daptomycin). U.S. Food & Drug Administration. July 29, 2010. Updated August 3, 2017. Accessed May 27, 2023. https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-eosinophilic-pneumonia-associated-use-cubicin-daptomycin
75. Ahouansou N, Georges M, Beltramo G, Aswad N, Hassani Y, Bonniaud P. Daptomycin-induced eosinophilic pneumonia: Are there any risk factors?. Infect Dis Now. 2021;51(7):618-621. doi:10.1016/j.idnow.2021.01.002
76. Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: Data from a randomized trial of patients with bacteremia and endocarditis. Clinical Infectious Diseases. 2010;50(12):1568-1574. doi:10.1086/652767
77. Fowler VG, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused bystaphylococcus aureus. New England Journal of Medicine. 2006;355(7):653-665. doi:10.1056/nejmoa053783
78. Dare RK, Tewell C, Harris B, et al. Effect of Statin Coadministration on the Risk of Daptomycin-Associated Myopathy. Clin Infect Dis. 2018;67(9):1356-1363. doi:10.1093/cid/ciy287
79. Tally FP, DeBruin MF. Development of daptomycin for gram-positive infections. Journal of Antimicrobial Chemotherapy. 2000;46(4):523-526. doi:10.1093/jac/46.4.523
80. Oleson FB Jr, Berman CL, Kirkpatrick JB, Regan KS, Lai JJ, Tally FP. Once-daily dosing in dogs optimizes daptomycin safety. Antimicrob Agents Chemother. 2000;44(11):2948-2953. doi:10.1128/AAC.44.11.2948-2953.2000
81. Dvorchik BH, Brazier D, DeBruin MF, Arbeit RD. Daptomycin pharmacokinetics and safety following administration of escalating doses once daily to healthy subjects. Antimicrob Agents Chemother. 2003;47(4):1318-1323. doi:10.1128/AAC.47.4.1318-1323.2003
82. Odero RO, Cleveland KO, Gelfand MS. Rhabdomyolysis and acute renal failure associated with the co-administration of Daptomycin and an HMG-COA reductase inhibitor. Journal of Antimicrobial Chemotherapy. 2009;63(6):1299-1300. doi:10.1093/jac/dkp127
83. Abo-Salem E, Fowler JC, Attari M, et al. Antibiotic-induced cardiac arrhythmias. Cardiovascular Therapeutics. 2014;32(1):19-25. doi:10.1111/1755-5922.12054
84. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine (Baltimore). 2003;82(4):282-290. doi:10.1097/01.md.0000085057.63483.9b
85. Cohagan B, Brandis D. Torsade de Pointes. StatPearls. Treasure Island, FL: StatPearls Publishing; 2023. https://www.ncbi.nlm.nih.gov/books/NBK459388/. Accessed March 14, 2023.
86. Freeman BD, Dixon DJ, Coopersmith CM, Zehnbauer BA, Buchman TG. Pharmacoepidemiology of QT-interval prolonging drug administration in critically ill patients. Pharmacoepidemiol Drug Saf. 2008;17(10):971-981. doi:10.1002/pds.1637
87. Curtis LH, Østbye T, Sendersky V, et al. Prescription of QT-prolonging drugs in a cohort of about 5 million outpatients. Am J Med. 2003;114(2):135-141. doi:10.1016/s0002-9343(02)01455-9
88. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther. 2003;73(4):292-303. doi:10.1016/s0009-9236(03)00009-2
89. Shaffer D, Singer S, Korvick J, Honig P. Concomitant risk factors in reports of torsades de pointes associated with macrolide use: review of the United States Food and Drug Administration Adverse Event Reporting System. Clin Infect Dis. 2002;35(2):197-200. doi:10.1086/340861
90. Kane SP. Erythromycin, ClinCalc DrugStats Database, Version 2022.08. Updated August 24, 2022. Accessed July 19, 2023. https://clincalc.com/DrugStats/Drugs/Erythromycin.
91. Justo D, Zeltser D. Torsades de pointes induced by antibiotics. Eur J Intern Med. 2006;17(4):254-259. doi:10.1016/j.ejim.2005.12.003
92. Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013-1022. doi:10.1056/NEJMra032426
93. Abo-Salem E, Nugent K, Chance W. Antibiotic-induced cardiac arrhythmia in elderly patients. J Am Geriatr Soc. 2011;59(9):1747-1749. doi:10.1111/j.1532-5415.2011.03552.x
94. Alves C, Mendes D, Marques FB. Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2019;75(10):1431-1443. doi:10.1007/s00228-019-02713-1
95. Baggio D, Ananda-Rajah MR. Fluoroquinolone antibiotics and adverse events. Aust Prescr. 2021;44(5):161-164. doi:10.18773/austprescr.2021.035
96. Khaliq Y, Zhanel GG. Fluoroquinolone-associated tendinopathy: a critical review of the literature. Clin Infect Dis. 2003;36(11):1404-1410. doi:10.1086/375078
97. Wildermuth A, Holmes M. A preventable, life-altering case of fluoroquinolone-associated tendonitis. JAAPA. 2022;35(11):33-36. doi:10.1097/01.JAA.0000873776.37967.9b
98. Tsai WC, Hsu CC, Chen CP, et al. Ciprofloxacin up-regulates tendon cells to express matrix metalloproteinase-2 with degradation of type I collagen. J Orthop Res. 2011;29(1):67-73. doi:10.1002/jor.211962010;29(1):67-73. doi:10.1002/jor.21196
99. Shakibaei M, de Souza P, van Sickle D, Stahlmann R. Biochemical changes in Achilles tendon from juvenile dogs after treatment with ciprofloxacin or feeding a magnesium-deficient diet. Arch Toxicol. 2001;75(6):369-374. doi:10.1007/s002040100243
100. Maan G, Keitoku K, Kimura N, et al. Cefepime-induced neurotoxicity: systematic review. J Antimicrob Chemother. 2022;77(11):2908-2921. doi:10.1093/jac/dkac271
101. Cefepime [package insert]. Lake Forest, IL: Hospira.; 2012
102. Li HT, Lee CH, Wu T, et al. Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study. Neurocrit Care. 2019;31(2):329-337. doi:10.1007/s12028-019-00682-y
103. Roger C, Louart B. Beta-Lactams Toxicity in the Intensive Care Unit: An Underestimated Collateral Damage?. Microorganisms. 2021;9(7):1505. Published 2021 Jul 14. doi:10.3390/microorganisms9071505
104. Chow KM, Hui AC, Szeto CC. Neurotoxicity induced by beta-lactam antibiotics: from bench to bedside. Eur J Clin Microbiol Infect Dis. 2005;24(10):649-653. doi:10.1007/s10096-005-0021-y
105. Amakhin DV, Soboleva EB, Zaitsev AV. Cephalosporin antibiotics are weak blockers of GABAa receptor-mediated synaptic transmission in rat brain slices. Biochem Biophys Res Commun. 2018;499(4):868-874. doi:10.1016/j.bbrc.2018.04.008
106. J10#. Sugimoto M, Uchida I, Mashimo T, et al. Evidence for the involvement of GABA(A) receptor blockade in convulsions induced by cephalosporins. Neuropharmacology. 2003;45(3):304-314. doi:10.1016/s0028-3908(03)00188-6
107. J7#. Triplett JD, Lawn ND, Chan J, Dunne JW. Cephalosporin-related neurotoxicity: Metabolic encephalopathy or non-convulsive status epilepticus?. J Clin Neurosci. 2019;67:163-166. doi:10.1016/j.jocn.2019.05.035
108. Deshayes S, Coquerel A, Verdon R. Neurological Adverse Effects Attributable to β-Lactam Antibiotics: A Literature Review. Drug Saf. 2017;40(12):1171-1198. doi:10.1007/s40264-017-0578-2
109. Fugate JE, Kalimullah EA, Hocker SE, Clark SL, Wijdicks EF, Rabinstein AA. Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy. Crit Care. 2013;17(6):R264. Published 2013 Nov 7. doi:10.1186/cc13094
110. Bhattacharyya S, Darby RR, Raibagkar P, Gonzalez Castro LN, Berkowitz AL. Antibiotic-associated encephalopathy [published correction appears in Neurology. 2016 May 31;86(22):2116]. Neurology. 2016;86(10):963-971. doi:10.1212/WNL.0000000000002455
111. Nakagawa R, Sato K, Uesaka Y, et al. Cefepime-induced encephalopathy in end-stage renal disease patients. J Neurol Sci. 2017;376:123-128. doi:10.1016/j.jns.2017.03.018
112. Boschung-Pasquier L, Atkinson A, Kastner LK, et al. Cefepime neurotoxicity: thresholds and risk factors. A retrospective cohort study. Clin Microbiol Infect. 2020;26(3):333-339. doi:10.1016/j.cmi.2019.06.028
113. Mattappalil A, Mergenhagen KA. Neurotoxicity with antimicrobials in the elderly: a review. Clin Ther. 2014;36(11):1489-1511.e4. doi:10.1016/j.clinthera.2014.09.020
114. Nguyen DD, Lai S. Prolonged Cefepime-Induced Neurotoxicity in a Patient with End-Stage Renal Disease. Am J Case Rep. 2022;23:e934083. Published 2022 Jan 24. doi:10.12659/AJCR.934083
115. French G. Safety and tolerability of linezolid. J Antimicrob Chemother. 2003;51 Suppl 2:ii45-ii53. doi:10.1093/jac/dkg253
116. Hashemian SMR, Farhadi T, Ganjparvar M. Linezolid: a review of its properties, function, and use in critical care. Drug Des Devel Ther. 2018;12:1759-1767. Published 2018 Jun 18. doi:10.2147/DDDT.S164515
117. Linezolid [package insert]. New York, NY: Pfizer Inc.; 2013
118. Kaya Kılıç E, Bulut C, Sönmezer MÇ, et al. Risk factors for linezolid-associated thrombocytopenia and negative effect of carbapenem combination. J Infect Dev Ctries. 2019;13(10):886-891. Published 2019 Oct 31. doi:10.3855/jidc.10859
119. Chen C, Guo DH, Cao X, et al. Risk factors for thrombocytopenia in adult chinese patients receiving linezolid therapy. Curr Ther Res Clin Exp. 2012;73(6):195-206. doi:10.1016/j.curtheres.2012.07.002
120. Natsumoto B, Yokota K, Omata F, Furukawa K. Risk factors for linezolid-associated thrombocytopenia in adult patients. Infection. 2014;42(6):1007-1012. doi:10.1007/s15010-014-0674-5
121. Hanai Y, Matsuo K, Ogawa M, et al. A retrospective study of the risk factors for linezolid-induced thrombocytopenia and anemia. J Infect Chemother. 2016;22(8):536-542. doi:10.1016/j.jiac.2016.05.003
122. Mayer MH, Dowsett SA, Brahmavar K, Kenneth Hornbuckle, Brookfield WP. Reporting adverse drug events. U.S. Pharmacist . April 19, 2010. Accessed July 11, 2023. https://www.uspharmacist.com/article/reporting-adverse-drug-events.
123. 4 Key Benefits of Reporting Adverse Events. GloShield. Published November 22, 2020. Accessed July 11, 2023. https://jackson-medical.com/benefits-of-reporting-adverse-events/
124. Code of Federal Regulations. Title 21, Chapter I, Subchapter D, Part 312 – Investigational New Drugs. Accessed July 19, 2023. eCFR :: 21 CFR Part 312 -- Investigational New Drug Application
125. Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment Clinical Medical. Food and Drug Administration. Published March 3, 2005. Accessed July 19, 2023. https://www.fda.gov/media/71546/download

LAW: THE OPIOID CRISIS: CAN REDUCING HARM SUPPLEMENT REDUCING SUPPLY?

The drug overdose crisis continues to worsen even as prescribing of controlled substances continues a decade long trend of decreasing. It is apparent that different strategies besides discouraging prescribing are necessary to reduce fatalities. One method is harm reduction which has been shown to be effective in addressing public health epidemics. Harm reduction approaches for drug overdose include medical treatment of opioid use disorder and measures to increase the safety of injectable drug use and can be enriched by pharmacist participation. This continuing education activity will review harm reduction approaches and discuss their application and the legal restrictions that may impede their implementation.

INTRODUCTION

“This downward trend (in life expectancy) could be reversed if we make progress in controlling the COVID-19 pandemic and opioid epidemic.”¹

--Robert H. Shmerling, MD, Senior Faculty Editor, Harvard Health Publishing

Data on life expectancy in the United States (U.S.) has been collected since 1900 and, with rare exceptions, has consistently increased.^1,2 Life expectancy in 1900 was 47 years, reached 68 years in 1950, and by 2019, had risen to 79 years.¹ However, in 2020 it fell to 77 and dropped again in 2021 to 76, the sharpest two-year decline in almost 100 years.^1,3

Many factors contributed to the decline in life expectancy in the U.S., which was not seen in other parts of the world. These include diseases of the heart and liver, but about two-thirds of the decline can be accounted for by increased rates of COVID-19, drug overdoses, and accidental deaths.^1,4 This reflects a continuation of disturbing trends in increases in what are termed “deaths of despair” (chronic pain, drug and alcohol dependency, and suicides).⁴

Harm reduction approaches have been shown to be effective in addressing public health epidemics including preventing death, injury, disease, overdose, and substance misuse.⁵ Harm reduction emphasizes direct engagement with people who use drugs to improve their physical, mental, and social well being, and prevent overdose and infectious disease transmission. It also simplifies accessing substance use disorder treatment and other health care services.⁵

Pharmacists have played an important role over the past few years in reducing the harm from COVID through vaccination, testing, and offering anti-viral drugs.⁵ Public health efforts to reduce tobacco consumption contributed significantly to the increase in life expectancy during the 1990s and 2000s, as fewer people died from complications related to smoking and nicotine.² Community pharmacists contributed to this successful effort by providing support to individuals trying to stop smoking.⁶ Can pharmacists also help reduce the harm associated with the record number of drug overdose deaths?

This continuing education activity will review some harm reduction strategies that may be useful in coping with the drug overdose epidemic and describes current legal and regulatory issues that may be barriers to more widespread application.

PAUSE AND PONDER: How can pharmacists reduce harm from opioids?

OPIOID CRISIS

Drug overdose deaths have become the number one cause of accidental deaths in the U.S., surpassing even motor vehicle mishaps.⁷ Deaths from drug overdose have risen dramatically, increasing from 16,849 in 1999 to a new record of 104,000 in the 12-month period ending February 2022.⁸ These numbers represented more than a 6-fold increase over this period. The overwhelming majority of drug overdose deaths are associated with an overdose of an opioid. In 2020, approximately three of four overdose deaths involved opioids,⁹compared with an opioid-related impact of 50% in 1999.¹⁰

The modern opioid crisis has occurred in three waves (so far). The first wave began in 1996 and was largely due to overdose from prescription opioids, fueled by what was perceived to be a widespread problem of undertreatment of chronic pain.¹¹ Health care providers began prescribing more opioid pain relievers and the increased supply and diversion to non-medical use created an opportunity for more overdoses.^11,12

This was addressed by clamping down on opioid prescribing. The overall national opioid dispensing rate significantly declined after 2012; by 2020, the dispensing rate had fallen to its lowest level in 15 years.⁶ Despite these efforts, overdose deaths from prescription opioids were higher in 2021 (16,706) than they were in 2012.¹³

Opioid overdose deathrates have continued to soar, suggesting that other factors have emerged and measures in addition to reducing supply are necessary to confront the epidemic.

The second wave began around 2010 as prescription opioids became harder to obtain and heroin’s price dropped; heroin became more attractive and popular.^12,14 The third and current wave started in 2013 and is associated with an increased supply of illicitly manufactured and trafficked synthetic opioids, especially fentanyl and its analogs.^12,14 (Evidence indicates a fourth wave is materializing characterized by polydrug abuse, typically the use of illegally manufactured opioids in combination with psychostimulants such as cocaine and methamphetamine.^12,15)

DECREASING SUPPLY

As noted, it was believed that an oversupply of prescription opioids was fueling the overdose crises. (Indeed, opioid prescriptions per capita increased 7.3% from 2007 to 2012 and 259 million prescriptions for opioid analgesics were written in 2012 alone, roughly one prescription for every adult in the U.S.¹⁶) Abatement efforts were geared towards reducing the supply and diversion of opioids. These “supply side” approaches include prescribing limits, prescription drug monitoring programs (PDMPs), and regulation of pain clinics.¹⁷

This approach corresponded with the development of an opioid prescribing guideline by the Centers for Disease Control and Prevention (CDC) in 2016, which provided recommendations for primary care clinicians prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care.¹⁶ The guideline’s focus on when to initiate or continue opioids for chronic pain; assessing risk and addressing harms of opioid use; and opioid selection, dosage, duration, follow-up, and discontinuation is detailed in Table 1.

Table 1. Summary of Centers for Disease Control and Prevention Guideline

Clinicians should

Prescribe the lowest effective dosage when initiating opioid therapy
Use caution when prescribing opioids at any dosage
Carefully reassess benefits and risks when increasing dosage to 50 morphine milligram equivalents (MME)/day
Avoid increasing dosage to 90 MME/day

Many states codified these voluntary recommendations through statutes or regulations that imposed enforceable limitations on medical professionals’ ability to prescribe or dispense opioids for pain treatment.¹⁸ The number of states with such restrictions increased from ten in 2016 to 39 by the end of 2019. States differed in their limits. At the end of 2019, the most common duration limit was seven days, with a range of three to 31. Fourteen states imposed limits on the daily dosage of opioids that could be prescribed, ranging from 30 MME to 120 MME.¹⁸

Enforced application of the CDC guideline, which was meant to serve as a guide for primary care providers, led to fewer opioid prescriptions along with reduced dosages, opioid tapering, and discontinuation of treatment among patients prescribed long-term opioid therapy.¹⁹ These actions resulted in multiple adverse outcomes including poor pain control and mental health issues for some patients. It forced many patients with pain to seek illicit sources as an alternative source of relief and resulted in an accompanying increase in overdose deaths.¹⁹

The most significant illicit substance emerging as the primary driver of the current overdose is fentanyl. Although technically a prescription drug, fentanyl’s primary source in overdose situations derives from illicit manufacture and importation.²⁰

Fentanyl is a powerful mu-opioid receptor agonist that is 75–100 times more potent than morphine.²¹Fentanyl rose to prominence as an alternative to morphine as an analgesic and anesthetic for surgeries more than 50 years ago due to its rapid onset, short duration of action, high potency, and limited cardiovascular risks compared to morphine. The potential for fentanyl misuse was initially believed to be minimal but it has emerged as a dangerous recreational substance.²¹ Although the media commonly describes it as a recent phenomenon, fentanyl has been used as a contaminant in illicit drug supplies since at least 1979.²² Fentanyl and its analogs have become the predominant factor in drug overdose deaths, accounting for almost two-thirds of overdose fatalities in 2021.²²

Fentanyl is sold by itself and is also used as an adulterant in other products due to its high potency which permits dealers to traffic smaller quantities that retain the expected opioid effect.^20,22 It is much more profitable for dealers to cut a kilogram of fentanyl compared to a kilogram of heroin. The drug is also made into counterfeit pills that resemble legitimate prescription opioids.²⁰ Since there is no regulatory oversight nor quality control, the pills can contain lethal quantities of fentanyl.²⁰

The COVID-19 pandemic made matters worse. Social isolation, loss of economic opportunity, boredom, despair, disruption of normal routines, and political polarization increased distress. Simultaneously, it became more difficult to access treatments, resources, and emergency services that help people suffering from opioid use disorder (OUD).^19,23,24 Lockdowns and distancing efforts made it less likely that an individual who overdosed would be discovered and given rescue naloxone in time to prevent lasting injury or death.²⁴ The decreased access to interventions and treatment led some patients to seek remedies on their own.¹⁹

In addition, COVID-19 mobility restrictions made it more challenging to smuggle illegal drugs into the country and border restrictions made it harder to move bulkier drugs.²⁵ As a result, smugglers increased their reliance on fentanyl which, due to its potency, can be transported in small quantities and is easier to traffic by mail.^22,25 This helped increase fentanyl’s availability in areas of the U.S. that had not previously been as impacted by the drug.²⁵ Prior to the pandemic, fentanyl mainly affected urban areas in the eastern regions of the U.S. where it could be easily mixed with the powdered heroin popular there.²⁵ Mortality rates from synthetic opioids more than doubled every two years in 28 states between 1999 and 2016; in Washington, D.C., mortality from opioids more than tripled every year from 2013-2016.²⁶

HARM REDUCTION MEASURES

It is apparent that reducing supply has had limited success in reversing the upward trend in overdose deaths. Could another strategy be more successful? It is generally believed that harm and demand reduction strategies can contribute to stemming the opioid overdose crisis.^5,17,23Relevant harm reduction activities that can lessen the risk of adverse outcomes associated with drug misuse include medical treatment of OUD, provision of sterile syringes, overdose prevention sites, fentanyl testing, safe supply, overdose education, expanded availability of naloxone, and Good Samaritan laws.^5,17,23 However, harm reduction approaches are underutilized; the CDC estimates that two-thirds of drug overdose deaths in 2021 had at least one potential opportunity for intervention.⁹

Medication Assisted Treatment of Opioid Use Disorder

Substance use disorders (SUD) are chronic conditions associated with many biologic, environmental, and social conditions.²⁷ SUD frequently co-occurs with other mental illnesses including depression, anxiety, and post-traumatic stress disorder; half of people with mental illnesses will have an SUD at some point in their lives.²⁷

OUD is a persisting and often relapsing condition requiring long-term care that is adjusted to meet individual patients’ needs by allowing changes in treatment designed to address fluctuations in symptomology.^27,28 OUD requires medical and psychosocial therapy similar to the treatment of other chronic disorders.^27,28 Opioid withdrawal, although very unpleasant and uncomfortable, is rarely life-threatening and is characterized by autonomic hyperactivity, and signs and symptoms which include anxiety, insomnia, nausea, vomiting, diarrhea, cramping, back pain, hot and cold flashes, and lacrimation.^27,28 Treatment is generally directed at alleviating these signs and symptoms of withdrawal.^27,28

Currently, three medications in the U.S. are Food and Drug Administration (FDA)-approved for use in Medication Assisted Treatment (MAT) of OUD: methadone, buprenorphine, and naltrexone.²⁹ Medically supervised withdrawal or detoxification can both improve the patient’s health and facilitate participation in a rehabilitation program.³⁰ It can also help patients accept abstinence from opioids after the acute withdrawal phase has subsided.³⁰

Traditionally, medically supervised withdrawal was only offered as a hospital-based treatment of varying duration. Today, medically supervised withdrawal is most often provided in outpatient and residential treatment settings and is usually managed by tapering doses of an opioid agonist or partial agonist over a period of between one week to several months.^27,28 Slower reductions over longer periods of time generally lead to less illicit use during the medically supervised withdrawal. Longer duration of treatment allows restoration of social connections and is associated with better outcomes.^28,31

Studies have suggested that MAT reduces overdose mortality by 3- to 4-fold, reduces the incidence of HIV and hepatitis-C transmission by half, doubles adherence to HIV antiviral therapy, and reduces drug-related crime.^27,28 However, it is usually not sufficient to produce long-term recovery by itself and may also increase the risk of overdose due to a loss of tolerance following abstinence.³⁰

Medically supervised withdrawal can also involve the use of nonopioid medications on an off-label basis to help control symptoms. α2-adrenergic agonists such as clonidine (Catapres), tizanidine (Zanaflex), or lofexidine (Lucemyra) can decrease anxiety, piloerection (erection or bristling of hairs due to the involuntary contraction of small muscles at the base of hair follicles, often called goose bumps), and other signs and symptoms of autonomic overactivity.^27,28,30 Adjunct therapy with medications such as anti-anxiety drugs, analgesics, sleep aids, anti-emetics, and anti-diarrheal products can also decrease the predominant withdrawal symptoms and decrease discomfort.^27,28

Long-Acting Opioid Agonists: Methadone and Buprenorphine

Prescribing a long-acting oral opioid, such as methadone or buprenorphine, is the most effective approach to treating a patient who is experiencing withdrawal.³⁰ These treatments relieve symptoms. Gradually reducing the dose allows the patient to adjust to the absence of an opioid.

Oral methadone has the strongest evidence for effectiveness. Methadone has been used since 1964 when it was introduced as a medical response to the post-War heroin epidemic in New York City and its use has spread to many countries.^27,28,32 Methadone is a full opioid agonist and N-methyl-D-aspartate receptor antagonist producing dose-dependent analgesia and sedation, with a risk of respiratory depression in overdose. It has a long half-life relative to abused forms of opioids, averaging about 24 hours with a variable range of 12-50 hours.³¹ It is typically delivered under direct daily supervision, at least initially, and treatment usually begins with a low dose that is slowly escalated.^27,28

Methadone maintenance is used to relieve narcotic craving, suppress the abstinence syndrome, and block the euphoric effects associated with opioids. Treatment occurs for an indefinite period, since methadone maintenance is considered corrective rather than curative for addiction.³²

When methadone is discontinued, it can lead to withdrawal which may be protracted due to its long duration of action.^27,28 Consequently, methadone treatment is gradually reduced over several weeks or months. Methadone is primarily metabolized by CYP3A (along with CYP2D6 and CYP1A2) and inhibitors and inducers of these enzymes can affect therapy.^27,28

Although methadone is highly effective as an MAT, it has certain disadvantages related to being a full mu-receptor agonist.³³ First, it has the potential to produce or maintain opioid dependence creating a risk of abrupt withdrawal if a patient misses a scheduled dose. This can be discouraging to patients who are trying to detoxify. In addition, there is no ceiling (or leveling off of effect) to the level of respiratory depression or sedation produced by a full agonist, and this can lead to fatal overdose.³³

An alternative to methadone is buprenorphine which has a different pharmacologic profile. It is a partial agonist at mu-opioid receptors, an antagonist of kappa and delta opioid receptors, and an agonist at opioid-like receptor-1 (nociceptin).³⁴ Despite being a partial agonist, it reportedly produces analgesic efficacy comparable to that of full μ-opioid receptor agonists in moderate to severe post-operative pain and pain associated with cancer.³⁴ It shares the beneficial properties of methadone being orally active with a long functional half-life (20 to 73 hours) and produces similar improvement of opioid withdrawal while producing less respiratory depression and sedation.³⁰ Buprenorphine maintenance may also result in a gentler withdrawal phase and the possible option of alternate-day dosing, due to its long duration of action.³⁴ However, as a partial agonist, it can produce a competitive antagonism of a concurrently administered full opioid agonist. Buprenorphine should be initiated at least 12 to 18 hours after the last dose of opioids in patients who misuse shorter-acting drugs to avoid precipitating abrupt and more intense withdrawal.³⁰

Buprenorphine is also available as a combination with the opioid antagonist naloxone, which minimizes intravenous misuse.³¹ Due to the low oral bioavailability of naloxone, it produces little opioid antagonism when the combination is taken orally or sublingually. However, if the preparation is crushed and injected, naloxone will block the reinforcing effects of buprenorphine and may also precipitate opioid withdrawal in a dependent individual.³¹

Studies comparing buprenorphine and methadone have reported mixed results, some showing no difference in efficacy between the two therapies, some showing methadone to be superior, and others finding buprenorphine to be superior.³³

Opioid Antagonists

Opioid antagonists block the reinforcing effects of opioids and help maintain opioid abstinence in highly motivated patients.³⁰ Naltrexone is an orally active long-acting mu- and kappa- opioid receptor antagonist, with effects lasting 24 to 36 hours.^27,28,30 It is also available as an extended-release intramuscular injectable form with effects lasting one month.³⁰ Oral naltrexone is used to treat both OUD and alcohol use disorder.³⁶ However, oral naltrexone is not commonly prescribed for OUD because there is poor compliance and evidence suggests that it may not be more effective than placebo in treating OUD. Since naltrexone can precipitate withdrawal in opioid-dependent individuals, it is recommended that patients wait at least seven days after their last use of short-acting opioids and 10 to 14 days for long-acting opioids, before starting naltrexone.^27,28,30,36 This presents a challenge for patients. An FDA-approved Risk Evaluation and Mitigation Strategy (REMS) that includes a Medication Guide is required for the long acting injectable, but it may otherwise be prescribed and administered by any practitioner licensed to prescribe.³⁶

Pharmacists are familiar with the protype opioid antagonist, naloxone, which is also an important harm reduction measure. Naloxone is a short acting antagonist originally used by injection to reverse opioid-induced postoperative respiratory depression and later used to reverse potentially fatal respiratory depression in individuals who overdosed on opioids.³⁶ Earlier rescue drugs such as nalorphine and levallorphan were partial agonists and, unlike naloxone, produced some respiratory depression.³⁷

Naloxone’s onset of action in adults is less than two minutes when administered intravenously, and its apparent duration of action is on the order of 20 to 90 minutes; significantly, this is a shorter duration than that of many opioid agonists⁸⁸ so that in some cases, the antagonism may decay before the agonist has been fully eliminated, placing users at risk of delayed respiratory depression.³⁹ In other words, naloxone reverses the effect of the agonist drug but since naloxone wears off quickly, there can still be sufficient drug in the system to re-initiate the toxicity.

Pharmacists should note that medication treatments are also being developed and evaluated for other types of drug misuse, such as naltrexone plus buprenorphine for methamphetamine use disorder.²⁷

Regulatory Issues

In the early 1900s, opiate drugs could be easily obtained from pharmacies. Diacetylmorphine, synthesized in 1874, was not often prescribed before 1900, but favorable reports of its effects stimulated interest from the medical profession.⁴⁰ The German pharmaceutical company Bayer (yes, the aspirin people) started commercial production of the compound in 1898 and marketed it under the name, “Heroin.”⁴⁰

Heroin was considered to be a “wonder drug” and the medical profession enthusiastically received it. The interest in heroin was prompted by the high occurrence of tuberculosis and other respiratory diseases and the need to find an effective remedy for cough and to induce sleep. Heroin was also believed to combat morphine addiction, but the inaccuracy of this approach became apparent after a few years.⁴⁰

The drug quickly caught the attention of criminal elements and smugglers who recognized that its rewarding properties surpassed those of morphine, the then-dominant abused drug.⁴⁰ Heroin also had the advantage of being able to be delivered by sniffing without the complications associated with intravenous injection.⁴⁰ A new societal problem emerged.

The Harrison Act passed in 1914 brought about one of the first federal controls on opioids. The Act regulated “narcotics” (defined as opiates and cocaine) by imposing a special tax upon anyone who produced, imported, manufactured, sold, dispensed, distributed, or compounded these substances.⁴¹ It mandated special order forms and record keeping whenever narcotic drugs were sold and products could only be provided from packages bearing a government stamp.⁴²

Physicians interpreted regulatory terms such "legitimate medical purposes," "professional practice," and "prescribed in good faith” to mean that they could provide narcotics to ease the suffering of withdrawal in addicts who were regarded as having a disease.⁴² However, the Treasury Department interpreted the Harrison Act to mean that any prescription for an addict for the purpose of relieving the trauma of addiction was illegal, and the Courts supported this position.⁴² Consequently, the only source available for an addict to obtain narcotics was through illegal means and physicians who used opioids to treat addicts risked federal and/or state criminal prosecution.^42,43 A law intended to regulate commerce effectively led to criminalization of OUD treatment.

In 1972 the US Food and Drug Administration (FDA) approved methadone treatment for OUD and established methadone maintenance as a legitimate medical practice.^43,44 However, concern about methadone diversion and accidental overdose fatalities, combined with political pressure from government agencies and groups committed to drug-free treatments, led to the development of detailed and unprecedented FDA regulations.⁴³ The Narcotic Addict Treatment Act in 1974 created the first federal law governing methadone for OUD while state and local governments placed additional regulatory requirements on methadone.^44,45 Congress granted the Drug Enforcement Agency (DEA) additional oversight of methadone treatment programs. Both the DEA and existing treatment providers have resisted efforts to relax the FDA regulations.⁴³

Administration of opioids to treat opioid-use disorders can only be performed by licensed addiction-treatment programs (either office-based or inpatient treatments) or by physicians who have completed specific opioid drug training.³⁰ Medical providers (physicians or advance practice providers such as physician assistants or nurse practitioners) may not use their DEA registration to prescribe methadone for OUD, but they can prescribe methadone tablets as a treatment for chronic pain.⁴⁵

Federal law also requires an in-person medical evaluation prior to patient enrollment in an opioid treatment program (OTP).⁴⁵ Initially, patients receiving methadone must return to the clinic a minimum of six days per week for medication administration with appropriate supervision for at least the first 90 days of treatment.⁴⁵ Afterwards, they can qualify for additional take-home doses under certain conditions. After the first 90 days the take home supply may increase to two doses per week. After 180 days, they may receive three take home doses per week. By 270 days, they may qualify for six take home doses per week for the remainder of the first year. In the second year of continuous treatment, a patient may be given a maximum 2-week supply of take-home medication. In the third year, a patient may be given a maximum one-month supply of take-home medication, but must make monthly visits. States have the authority to further restrict administration and dispensing policies.^44.45

However, in response to the COVID-19 pandemic, some impediments to methadone treatment were relaxed. In March 2020, the Substance Abuse and Mental Health Services Administration (SAMHSA) issued guidance allowing states to request that patients who are on a stable methadone dose be permitted to receive 28 days of take-home medication, and for patients who are less stable to receive 14 days of take-home medication.²⁴

In contrast, buprenorphine can be prescribed by certified physicians, without the requirement for direct supervision of administration since diversion is associated with significantly less risk of fatal overdose than methadone.³¹

Patients being treated with MAT also encounter the restrictions of the Ryan Haight Act, named after a minor who overdosed on a controlled substance he obtained over the Internet with a prescription from a physician who did not conduct a proper medical examination. The law requires practitioners issuing a prescription for a controlled substances to first conduct an in-person medical evaluation.⁴⁶

During the COVID public health emergency, the DEA waived the requirement that patients receiving buprenorphine must have an in-person consultation with a prescriber and permitted the consultation to occur via telemedicine.²⁴

PAUSE AND PONDER: Should pharmacists be involved in facilitating access to OUD medications?

The Drug Addiction Treatment Act of 2000 (DATA) was enacted to permit physicians who meet certain qualifications to treat opioid dependence with FDA-approved C-III – C-V opioid medications, including buprenorphine, in treatment settings other than OTPs.⁴⁷ DATA restricted the outpatient treatment of OUD with buprenorphine to clinicians receiving an “X- [or DATA] waiver.”⁴⁸ To receive the waiver, clinicians were required to attend an eight hour training session and submit a Notice of Intent to SAMHSA; other eligible practitioners, including nurse practitioners and physician assistants, were required to obtain an additional 16 hours of training.^48,49 Pharmacists and X Prescriptions were required to have the prescribers’ X-number in addition to their DEA registration number and pharmacists were expected to verify a practitioner's certification, but there were no other requirements for pharmacists beyond those for other Schedule III medications, such as special credentials.

In 2023, the Mainstreaming Addiction Treatment Act (MAT Act) eliminated the need for a special waiver to treat patients with OUD.⁵⁰ Any practitioner with current DEA registration that includes Schedule III authority may prescribe buprenorphine for OUD. The MAT Act also removed other federal requirements associated with the waiver. However, pharmacists should be aware that state requirements may differ.⁴⁹

Naloxone has also transitioned, becoming a more readily available substance. The FDA approved naloxone in 1971 as a prescription-only medication for intravenous, intramuscular, and subcutaneous administration to reverse postoperative respiratory depression induced by opioid analgesics.^36,51 Overdose rescue was originally limited to emergency departments, but its use expanded to first responders and distribution by community groups to individuals with OUD or their family and acquaintances for emergency use.⁵² Reluctance to administer the drug with a needle led to improvised homemade intranasal naloxone delivery devices.⁵¹ FDA approval of a standardized, pre-assembled intranasal delivery form in 2015 significantly improved and simplified naloxone use.⁵³ Pharmacists in all states were also granted authority to dispense naloxone through collaborative agreements or blanket standing orders.⁵⁴The FDA approved naloxone for OTC distribution in 2023.⁵⁵

Safer Injection

Another harm reduction strategy is to make the experience of injecting opioids safer. Several different approaches may enhance the safety of injections.

Needle/Paraphernalia Exchange

Syringe services programs (SSPs) are community-based prevention programs which are thought to be a critical component of harm reduction interventions for injectable drug users.^56,57 SSPs provide access to and disposal of sterile syringes and injection equipment and may also include offering referrals to medication-assisted treatment, as well as vaccination, testing, and links to care and treatment for infectious diseases.⁵⁶ The majority of new hepatitis C virus infections are related to injection drug use and 10% of new HIV infections in the U.S. are attributed to injection drug use. Infections occur because needles, syringes, or other equipment used for injections may be contaminated with blood that can carry viruses. HIV can survive in a used syringe for up to 42 days, depending on temperature and other factors.⁵⁸ In addition, people under the influence of substances are more likely to engage in risky sexual behaviors which can increase the risk of transmitting an infection.^56,57

SSPs have the added benefit of protecting the public and first responders by facilitating the safe disposal of used needles and syringes. Many SSPs also provide “overdose prevention kits” containing naloxone.^56,58

Safe Injection Facilities

Safe injection facilities (SIF; AKA overdose prevention centers, supervised consumption services, supervised injection facilities, drug consumption rooms, or safe havens) provide a sanctioned, safe space where people can inject drugs obtained elsewhere in a controlled setting under the supervision of trained staff with a goal of preventing fatal overdoses.^59,60 Staff at the facility do not directly assist with injections or handle any drugs brought in by clients, but are present to provide sterile injection supplies, answer questions on safe injection practices and vein care, administer first aid if needed, and monitor for overdose. Participants can also receive health care and general medical advice, counseling, and referrals to health and social services, including drug treatment options.^59,60

SIFs have operated in Europe since the 1980s.⁵⁹ They generally target high-risk, socially marginalized injectable drug users who would otherwise inject in public spaces or shooting galleries. Reports generally show that SIFs have led to fewer risky injection behaviors and fewer overdose deaths among clients, increased enrollment in drug treatment services, and reduced the incidence of public nuisances associated with open injection.⁵⁹ Although SSPs reduce the risks associated with contaminated needles and syringes, they do not address the harm created by users’ fear of the criminal justice system and stigma.⁵⁹

In the U.S., states and some municipalities have the power to authorize SIFs under state law, However, they are still prohibited by the federal Controlled Substances Act.^59,81A Philadelphia non-profit planned to open consumption sites where individuals could inject controlled substances under supervision, but the Department of Justice (DOJ) sought to prevent it.⁶¹ The DOJ argued that a “consumption room” is intended to be a place where people consume drugs and would therefore be in violation of the CSA which prohibits any person from knowingly and intentionally maintaining a place for the purpose of illegal drug use. The District Court ruled that the CSA does not apply, but the decision was reversed on appeal. The Appellate Court ruled that the safehouse would violate the law because people will visit its facility with the purpose of using drugs. The law requiring CSA oversight of places where there is illegal drug use was originally passed to shut down crack houses. Despite the organization’s “admirable” motives and the need for “innovative solutions” to combat the opioid crisis, the court held that “courts are not arbiters of policy” and “local innovations may not break federal law.”⁶¹ The decision was appealed to the Supreme Court, but they rejected the request to hear the case; some issues are still pending.

In November 2021, New York City opened the first supervised injection site in the U.S., six weeks after the Supreme Court decision.⁶² In its first three months, approximately 800 people used the center more than 9500 times and it averted at least 150 overdoses. The site supplies syringes, alcohol wipes, straws for snorting, other paraphernalia, and oxygen and naloxone in case of an overdose.⁶² A few other cities and the state of Rhode Island have also established a pilot program for safe injection sites.⁶²

Despite the results in the Philadelphia court case, the DOJ has indicated a willingness to relax its opposition to safe sites, saying that it was evaluating them and discussing “appropriate guardrails.”⁶² Some members of Congress have expressed opposition to permitting sites to operate and a former DEA official has stated that “the goal has to be to stop doing drugs” and encourage treatment.⁶²

Safer Supply Prescribing

Another possible risk mitigation approach that could impact pharmacists is safer supply prescribing. This expanding movement in Canada allows prescribers at recognized sites to write prescriptions for government-funded, pharmaceutical-grade products, primarily opioids.^63,64 The most commonly offered products at the sites studied were injectable and tablet hydromorphone, and medical grade heroin.⁶³ Some clinics are supplying pharmaceutical-grade fentanyl to offset the unregulated street supply.⁶⁴ One site delivers medication to multiple clients quarantined in a motel.⁶³

Pharmacy models included hospital-based pharmacies and partnerships with a service site to either provide the site with medication or provide it directly to clients.⁶³ In some instances, users can select their own pharmacy. There are also machine-dispensed services offering prescribed opioids for up to 15 clients without the barriers of daily observation or check-ins.

This practice is currently illegal in the U.S. but has its advocates such as a Yale addiction medicine physician who said “(w)e need to be doing everything possible to try, at a minimum, to make a dent in the unrelenting deaths that in large part have been due to changes in the unregulated drug supply.”⁶⁴

Some preliminary studies have suggested that these programs can lower overdose risk. Providing drugs to participants when other treatment strategies haven’t worked can reduce illicit drug use, reduce emergency department visits and hospital admissions, and connect users to care.⁶⁴

Critics, including addiction specialists, argue that users should be directed toward treatment for their dependence and that providers should focus on reducing drug use rather than providing drugs. Some people are concerned about the potential for diversion and have likened these programs to the overprescribing of opioids that initially helped fuel the overdose crisis.⁶⁴

PAUSE AND PONDER: Would you participate in a safe supply program?

Test Kits

Another approach to harm reduction is the use of test strips that can detect contaminants such as fentanyl in street drug samples.⁶⁵ Test strips are prefabricated strips of a carrier material containing dry reagents that are activated by applying a fluid sample. They can detect the presence of substances within a matter of minutes.⁶⁶ Strips are available to detect many different illicit drugs and are similar to commonly used test kits for detecting pregnancy, failure of internal organs (e.g., heart attack, renal failure, or diabetes), infection or contamination with specific pathogens, or the presence of toxic compounds in food or the environment.⁶⁶ The strips rely on a lateral flow chromatographic immunoassay technology for the qualitative detection of fentanyl and many analogs at concentrations above 200 ng/mL.⁶⁷ The strips have no significant cross reactivity to other opiates and the interpretation of test results is simple: positive (one line), negative (two lines), invalid (no lines or no control line).⁶⁷

The strips were created in 2011 to detect prescription fentanyl in urine as part of a clinical identification of recent drug use. As fentanyl was found more frequently in analyses from drug overdoses, the harm reduction community began using the tests off-label, especially in syringe services sites, to test samples. This empowered drug users to understand what substances they were consuming, making them safer.⁶⁸ A study of drug users in North Carolina found that receiving a positive test result was associated with changes in drug use behavior and perceptions of overdose safety.⁶⁸ Behavioral changes included using less drug, administering a test shot, injecting more slowly, or snorting the sample instead of injecting it. They introduce an element of caution for the drug user.⁶⁹

The use of test strips is restricted in many areas. It is clearly legal to possess some or all drug checking equipment in 22 states, and clearly legal to distribute it to adults in 19 states.⁶⁵ In 14 states where distribution of drug checking equipment is not generally legal, it is legal when the equipment is obtained from a syringe services program.⁶⁵ Tools used to detect fentanyl are classified as drug paraphernalia in more than a dozen states, making it a crime to possess or distribute them.⁷⁰ These state laws emerged in the 1970s at the urging of the DEA claiming that distributing paraphernalia serves to facilitate drug use. Many states continue to maintain a hardline posture.⁷⁰ While laws define drug paraphernalia broadly, they are not always rigorously enforced.⁶⁸ However, violators may face potential penalties ranging from small civil fines to multi-year jail sentences.⁶⁵

PAUSE AND PONDER: What reservations might you have about advising a patient to purchase fentanyl test strips?

Although these devices have some legal restrictions, demand in the U.S. has grown more than 430% in the past three years.⁷¹ They are becoming available in clubs, bars, restaurants, and pizza shops and are frequently distributed for free. Some advocates equate strips to condoms as a public health measure. The FDA warns that it doesn’t actively regulate fentanyl test strips, which places the burden of determining their reliability on buyers.

The strips are available from Amazon and can be obtained from public vending machines in some areas.

SUMARY AND CONCLUDING COMMENTS

The opioid overdose crisis continues to worsen. Despite many efforts over the past decade to reduce the supply of prescription opioids, overdose deaths continue to climb from drugs obtained via illicit sources. While efforts to reduce supply continue, there are also attempts to institute harm mitigation programs. However, existing laws and regulations can make accessing these measures difficult.

Recent efforts have eased the prescribing and use of MAT. This provides pharmacists with a potential opportunity to become more involved with SUD treatment. MAT is underutilized with evidence suggesting that only 13% of people with drug use disorders receive any treatment, and more than half of those with co-occurring conditions receive treatment for neither. Other measures involving pharmacists include increased naloxone access, and availability of test kits in pharmacies.

More controversial models have also gained some acceptance, but strong opposition remains. Pharmacists are or may become involved with programs such as needle/syringe exchange, safe sites, and, as aways, there are opportunities for education and counseling. Pharmacists should also be prepared for the possible, albeit unlikely, introduction of the Canadian model of supplying pharmaceutical grade opioids and other controlled substances to users.

Pharmacists have demonstrated value in implementing harm reduction strategies for many disease states and interested pharmacists should be prepared to be involved with the growing number of opportunities to reduce the opioid overdose crisis.

POST-TEST

OBJECTIVES:
After completing this activity, participants should be better able to:
1. Review how controlling the supply of opioids has affected the drug overdose crisis.
2. Describe strategies that reduce the harm from misusing opioids.
3. Discuss how medication assisted treatment of opioid use disorder reduces overdose risk.
4. Characterize how regulatory decisions affect access to harm reduction measures.

1. According to CDC estimates, what percentage of drug overdose deaths in 2021 had at least one potential opportunity for intervention?
A. 25%
B. 50%
C. 67%

2. What is currently driving the drug overdose crisis?
A. Prescription opioids
B. Heroin
C. Illicitly manufactured fentanyl

3. In what year did the prescribing of opioids reach its peak?
A. 2012
B. 2019
C. 2021

4. How did the 1914 Harrison Act change the distribution of opiate medications?
A. It made it illegal to prescribe heroin.
B. It created the five schedules of controlled substances.
C. Any prescription for addicts to relieve addiction trauma was illegal.

5. What is an advantage of buprenorphine compared with methadone for opioid use disorder?
A. Buprenorphine is more effective than methadone in treating OUD.
B. Buprenorphine is less likely to produce respiratory depression than methadone if misused.
C. Buprenorphine is less likely to precipitate withdrawal than methadone when administered to someone who is currently misusing street opioids.

6. The DEA recently modified the regulations for buprenorphine. What did they do?
A. They eliminated the requirement for a special (X-) waiver to prescribe buprenorphine for OUD.
B. They reduced the number of patents that a prescriber may treat with buprenorphine at any one time.
C. They created special licensure to permit certified pharmacist to prescribe buprenorphine for OUD.

7. Approximately what percentage of people with substance use disorders receive any treatment in the U.S.?
A. 13%
B. 25%
C. 50%

8. A patient with OUD has been offered naltrexone at his treatment clinic and asks you if it differs from the naloxone that he picked up at the pharmacy last week. What could you tell him?
A. Naltrexone is longer acting than naloxone.
B. Naltrexone can only be administered by IV injection at the clinic.
C. Naltrexone effects are similar to methadone’s.

9. What is the Canadian Safe Prescribing model?
A. Removing restrictions on prescribing methadone for OUD.
B. Prescribing pharmaceutical grade heroin.
C. Making buprenorphine over-the-counter in pharmacies.

10. A patient enters the pharmacy looking for fentanyl test strips, but you practice in a state where they are illegal to purchase. Why are fentanyl test strips illegal in some states?
A. They have not been approved by the Food and Drug Administration.
B. They are considered drug paraphernalia that facilitates drug use.
C. There is no evidence that the strips alter risky behavior in drug users.

REFERENCES

Shmerling RH. Why Life Expectancy in The US Is Falling. Harvard Health. October 20,2022. Accessed October 23, 2023.

https://www.health.harvard.edu/blog/why-life-expectancy-in-the-us-is-falling-202210202835

Sheridan K. U.S. Life Expectancy Drops Sharply, The Second Consecutive Decline. Stat News. August 31, 2022. Accessed October 23, 2023. https://www.statnews.com/2022/08/31/u-s-life-expectancy-drops-sharply-the-second-consecutive-decline/
Rabin RC. U.S. Life Expectancy Falls Again in ‘Historic’ Setback. NY Times. August 31, 2022. Accessed October 23, 2023. https://www.nytimes.com/2022/08/31/health/life-expectancy-covid-pandemic.html
Perry S. Life Expectancy in U.S. Falls; Opioids and Other ‘Deaths Of Despair’ Explain Part Of The Drop. Minn Post. August 20, 2018. Accessed October 23, 2023. https://www.minnpost.com/second-opinion/2018/08/life-expectancy-us-falls-opioids-and-other-deaths-despair-explain-part-drop/
Substance Abuse and Mental Health Services Administration. Harm Reduction. Updated August 16, 2022. Accessed October 23, 2023. https://www.samhsa.gov/find-help/harm-reduction
Carson-Chahhoud KV, Livingstone-Banks J, Sharrad KJ, et al. Community pharmacy personnel interventions for smoking cessation. Cochrane Database Syst Rev. 2019(10):CD003698.
National Safety Council. For the First Time, We’re More Likely to Die From Accidental Opioid Overdose Than Motor Vehicle Crash. January 14, 2019. Accessed October 23, 2023. https://www.nsc.org/in-the-newsroom/for-the-first-time-were-more-likely-to-die-from-accidental-opioid-overdose-than-motor-vehicle-crash
Centers for Disease Control and Prevention, National Center for Health Statistics. Provisional Overdose Death Counts. Updated February 9, 2022. Accessed October 23, 2023. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm
Centers for Disease Control and Prevention. SUDORS Dashboard: Fatal Overdose Data. Accessed October 23, 2023. https://www.cdc.gov/drugoverdose/fatal/dashboard/index.html
National Institute on Drug Abuse. Overdose Death Rates. January 20, 2022. Accessed October 23, 2023. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
Sosin D. Examining the Growing Problems of Prescription Drug and Heroin Abuse. Testimony before the Oversight and Investigations Subcommittee Energy and Commerce Committee U.S. House of Representatives. April 29, 2014. Accessed October 23, 2023. https://docs.house.gov/meetings/IF/IF02/20140429/102161/HHRG-113-IF02-Wstate-SosinD-20140429.pdf
Liu L, Pei DN, Soto P. History of the Opioid Epidemic. How Did We Get Here? National Capital Poison Center. Accessed October 23, 2023. https://www.poison.org/articles/opioid-epidemic-history-and-prescribing-patterns-182
National Institute on Drug Abuse. Overdose Death Rates. Accessed October 23, 2023. https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates
Centers for Disease Control and Prevention. Understanding the Opioid Overdose Epidemic. June 1, 2022. Accessed October 23, 2023. https://www.cdc.gov/opioids/basics/epidemic.html
Ciccarone D. The Rise of Illicit Fentanyls, Stimulants and the Fourth Wave of the Opioid Overdose Crisis. Curr Opin Psychiatry. 2021;34(4):344-350.
Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain — United States, 2016. MMWR Recomm Rep. 2016;65:1–49.
Lee B, Zhao W, Yang KC, Ahn YY, Perry BL. Systematic Evaluation of State Policy Interventions Targeting the US Opioid Epidemic, 2007-2018. JAMA Netw Open. 2021;4(2):e2036687.
Network for Public Health Law. Laws Limiting the Prescribing or Dispensing of Opioids. Accessed October 23, 2023. https://www.networkforphl.org/wp-content/uploads/2021/05/50-State-Survey-Laws-Limiting-the-Prescribing-or-Dispensing-of-Opioidspf-CSD_FINAL.pdf
Manchikanti L, Singh VM, Staats PS, et al. Fourth Wave of Opioid (Illicit Drug) Overdose Deaths and Diminishing Access to Prescription Opioids and Interventional Techniques: Cause and Effect. Pain Physician. 2022;25(2):97-124.
Drug Enforcement Administration. Facts About Fentanyl. Accessed October 23, 2023. https://www.dea.gov/resources/facts-about-fentanyl
Burns SM, Cunningham CW, Mercer SL. DARK Classics in Chemical Neuroscience: Fentanyl. ACS Chem Neurosci. 2018;9(10):2428-2437.
Babu K. What Is Fentanyl and Why Is It Behind the Deadly Surge in US Drug Overdoses? A Medical Toxicologist Explains. The Conversation. May10, 2022. Accessed October 23, 2023. https://theconversation.com/what-is-fentanyl-and-why-is-it-behind-the-deadly-surge-in-us-drug-overdoses-a-medical-toxicologist-explains-182629
Wakeman S. We're Approaching the Overdose Crisis All Wrong. MedPage Today. August 16, 2022. Accessed October 23, 2023. https://www.medpagetoday.com/opinion/second-opinions/100250?xid=nl_secondopinion_2022-08-21&eun=g1359385d0r
Davis, C. & Samuels, E. Opioid Policy Changes During the COVID-19 Pandemic - and Beyond. J Addiction Med. 2020;14(4): e4-e5.
Kolodny A. Fentanyl Spread Across the US During the Pandemic. This Is Why. Brandeis Now. November 26, 2021. Accessed October 23, 2023. https://www.brandeis.edu/now/2021/november/fentanyl-pandemic-kolodny.html
Kiang MV, Basu S, Chen J, Alexander MJ. Assessment of Changes in the Geographical Distribution of Opioid-Related Mortality Across the United States by Opioid Type, 1999-2016. JAMA Netw Open.2019;2(2):e190040.
Volkow ND. Strengthening Federal Mental Health and Substance Use Disorder Programs:

Opportunities, Challenges, and Emerging Issues. Testimony before the Senate Health, Education, Labor and Pensions Committee. March 23, 2022. Accessed October 23, 2023. https://www.help.senate.gov/imo/media/doc/Volkow.pdf

Strang J, Volkow ND, Degenhardt L, et al. Opioid use disorder. Nat Rev Dis Primers. 2020;6(1):3.
Medications for Opioid Use Disorder Improve Patient Outcomes. Pew Foundation. December 17, 2020. Accessed October 23, 2023. https://www.pewtrusts.org/en/research-and-analysis/fact-sheets/2020/12/medications-for-opioid-use-disorder-improve-patient-outcomes
Schuckit M. Treatment of Opioid-Use Disorders. N Engl J Med. 2016;375:357-368.
Bell J, Strang JS. Medication Treatment of Opioid Use Disorder. Biol Psychiatry. 2020;87(1):82-88.
Joseph H, Stancliff S, Langrod J. Methadone Maintenance Treatment (MMT): A Review of Historical and Clinical Issues. Mt Sinai J Med. 2000;67(5-6):347-364.
M Mattick RP, Breen C, Kimber J, Davoli M. Buprenorphine Maintenance Versus Placebo Or Methadone Maintenance For Opioid Dependence. Cochrane Database of Systematic Reviews 2014, Issue 2. Art. No.: CD002207.
Gudin J, Fudin J. A Narrative Pharmacological Review of Buprenorphine: A Unique Opioid for the Treatment of Chronic Pain. Pain Ther. 2020;9(1):41-54.
Substance Abuse and Mental Health Services Administration. Naltrexone. Accessed October 23, 2023. https://www.samhsa.gov/medications-substance-use-disorders/medications-counseling-related-conditions/naltrexone
van Dorp E, Yassen A, Dahan A. Naloxone Treatment in Opioid Addiction: The Risks and Benefits. Expert Opin Drug Saf. 2007;6(2):125-132.
Jasinski DR. Human Pharmacology of Narcotic Antagonists. Br J Clin Pharmacol. 1979;7(Suppl 3):287S-290S.
Wanger K, Brough L, Macmillan I, Goulding J, MacPhail I, Christenson JM. Intravenous vs Subcutaneous Naloxone for Out-Of-Hospital Management Of Presumed Opioid Overdose. Acad Emerg Med. 1998;5(4):293–299.
Skolnick P. Treatment of overdose in the synthetic opioid era. Pharmacol Therap. 2022; 233:108019.
United Nations Office on Drugs and Crime. History of Heroin. Accessed October 23, 2023.

https://www.unodc.org/unodc/en/data-and-analysis/bulletin/bulletin_1953-01-01_2_page004.html

Spillane JF. Debating the Controlled Substances Act. Drug Alcohol Depend. 2004;76(1):17-29.
Cantor DJ. The Criminal Law and the Narcotics Problem. J. Crim. L. Criminology & Police Sci. 1961;51(5):512-527.
43. Jaffe JH, O'Keeffe C. From Morphine Clinics to Buprenorphine: Regulating Opioid Agonist Treatment of Addiction in the United States. Drug Alcohol Depend. 2003;70(Suppl2):S3-S11.
Joudrey PJ, Bart G, Brooner RK, Brown L, et al. (2021) Research Priorities For Expanding Access To Methadone Treatment For Opioid Use Disorder In The United States: A National Institute On Drug Abuse Clinical Trials Network Task Force Report, Substance Abuse 2021;42(3):245-254.
Joudrey PJ, Gordon AJ. Inflexible Methadone Regulations Impede America’s Efforts to Reduce Overdose Deaths. Stat News. Dec. 22, 2021. Accessed October 23, 2023. https://www.statnews.com/2021/12/22/inflexible-methadone-regulations-impede-efforts-reduce-overdose-deaths/
Drug Enforcement Administration. Temporary Extension of COVID-19 Telemedicine Flexibilities for Prescription of Controlled Medications. Fed Reg. 2023;88:30037-30043.
Manlandro JJ Jr. Buprenorphine for Office-Based Treatment of Patients With Opioid Addiction. J Am Osteopath Assoc. 2005;105(Suppl 3):S8-S13.
Stringfellow EJ, Humphries J, Jalali MS. Removing The X-Waiver Is One Small Step Toward Increasing Treatment of Opioid Use Disorder, But Great Leaps Are Needed. Health Affairs. April 22, 2021. Accessed October 23, 2023. https://www.healthaffairs.org/content/forefront/removing-x-waiver-one-small-step-toward-increasing-treatment-opioid-use-disorder-but
Substance Abuse and Mental Health Services Administration. Statutes. Regulations and Guidelines. Accessed October 23, 2023. https://www.samhsa.gov/medication-assisted-treatment/statutes-regulations-guidelines#mobile
Substance Abuse and Mental Health Services Administration. Waiver Elimination (MAT Act).

Accessed October 23, 2023. https://www.samhsa.gov/medications-substance-use-disorders/waiver-elimination-mat-act

Strang J, McDonald R, Campbell G, et al. Take-Home Naloxone for the Emergency Interim Management of Opioid Overdose: The Public Health Application of an Emergency Medicine. Drugs. 2019;79(13):1395-1418.
Davis CS, Carr D. Legal changes to increase access to naloxone for opioid overdose reversal in the United States. Drug Alc Depen. 2015;157:112-120.
U.S. Food and Drug Administration. FDA Moves Quickly to Approve Easy-To-Use Nasal Spray To Treat Opioid Overdose. November 18, 2015. Accessed October 23, 2023. https://wayback.archive-it.org/7993/20180125101447/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm473505.htm
State Naloxone Access Rules and Resources. SafeProject. Accessed October 23, 2023. https://www.safeproject.us/naloxone/awareness-project/state-rules/?hmpid=c3luYXBzZTIyMEBob3RtYWlsLmNvbQ==&utm_medium=email&utm_source=enewsletter&utm_content=1696034347
U.S. Food and Drug Administration. FDA Approves First Over-the-Counter Naloxone Nasal Spray. March 29, 2023. Accessed October 23, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray
Centers for Disease Control and Prevention. Syringe Service Programs (SSPs). May 23, 2019. Accessed October 23, 2023. https://www.cdc.gov/ssp/index.html
Fernandes RM, Cary M, Duarte G, et al. Effectiveness of Needle And Syringe Programmes In People Who Inject Drugs - An Overview Of Systematic Reviews. BMC Public Health. 2017;17(1):309.
Centers for Disease Control and Prevention. HIV and Injection Drug Use. Accessed October 23, 2023.

https://www.cdc.gov/hiv/basics/hiv-transmission/injection-drug-use.html

Beletsky L, Davis CS, Anderson E, Burris S. 2008: The Law (and Politics) of Safe Injection Facilities in the United States. Am J Public Health. 2008;98:231-237.
Finke J, Chan J. The Case for Supervised Injection Sites in the United States. Am Fam Physician. 2022;105(5):454-455.
U.S. Department of Justice. Appellate Court Agrees with Government that Supervised Injection Sites are Illegal under Federal Law; Reverses District Court Ruling. January 13, 2021. Accessed October 23, 2023. https://www.justice.gov/opa/pr/appellate-court-agrees-government-supervised-injection-sites-are-illegal-under-federal-law
Peltz J. A Look Inside the 1st Official Safe Injection Sites in U.S. AP/PBS. March 9, 2022. Accessed October 23, 2023. https://www.pbs.org/newshour/health/a-look-inside-the-1st-official-safe-injection-sites-in-u-s
Glegg S, McCrae K, Kolla G, Touesnard N, et al. “COVID just kind of opened a can of whoop-ass”: The rapid growth of safer supply prescribing during the pandemic documented through an environmental scan of addiction and harm reduction services in Canada. Int J Drug Policy. 2022;106:103742.
Joseph A. ‘This Program’s Really Saved Us’: As Canada Offers Safer Opioids to Curb Overdoses, Will U.S. Follow? Stat News. September 21, 2022. Accessed October 23, 2023. https://www.statnews.com/2022/09/21/canada-giving-out-safer-opioids-to-stem-overdoses-will-u-s-follow/
Davis CS, Judd Lieberman A, O’Kelley-Bangsberg M. Legality of Drug Checking Equipment In The United States: A Systematic Legal Analysis. Drug Alc Depend. 2022;234:109425.
Trumpie P, Korf GA, van Amerongen J. A. Lateral flow (immuno)assay: its strengths, weaknesses, opportunities and threats. A literature survey. Anal Bioanal Chem. 2009;393:569–582.
BTNX. Harm Reduction. Accessed October 23, 2023. https://www.btnx.com/HarmReduction
D’Ambrosio A. More States Legalize Fentanyl Test Strips. MedPage Today. March 28, 2022. Accessed October 23, 2023. https://www.medpagetoday.com/special-reports/exclusives/97900
Peiper NC, Duhart Clarke S, Vincent LB, Dan Ciccarone D, et al. Fentanyl Test Strips as An Opioid Overdose Prevention Strategy: Findings From A Syringe Services Program in the Southeastern United States. Int J Drug Policy. 2019;63:122-128.
Facher L. Fentanyl Test Strips Could Help Save Lives. In Many States, They’re Still Illegal. Stat News.

September 8, 2022. Accessed October 23, 2023. https://www.statnews.com/2022/09/08/fentanyl-test-strips-could-help-save-lives-in-many-states-theyre-still-illegal/

O’Brien A, Wernau J. Fentanyl Test Strips on the Dance Floor? Partygoers Face New Reality. WSJ. January 18, 2023. Accessed October 23, 2023. https://www.wsj.com/articles/fentanyl-test-strips-party-culture-bars-restaurants-testing-11673993170?mod=djem10point

Patient Safety: Gabapentin and Trazadone: Off-label Use is Out of Control-Recorded Webinar

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this knowledge-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-044-H05-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Patient Safety: Gabapentin and Trazodone, Off-label Use is Out of Control
LEARNING OBJECTIVES
At the end of this continuing education activity, pharmacists will be able to
1. LIST the numerous off label uses of gabapentin and trazodone
2. DESCRIBE which of those uses are supported by actual evidence
3. INDICATE the potential adverse effects and medication related problems that patients who take these drugs may experience
4. ARTICULATE ways to approach prescribers with alternative suggestions

1. Which of the following is an off-label use for gabapentin?
A. Postherpetic neuralgia
B. Adjunctive therapy in partial seizures
C. Migraine prophylaxis

2. Which of the following is an off-label use for trazodone?
A. Chronic insomnia
B. Major depressive disorder
C. Pruritis

3. Which of gabapentin’s off-label uses has the strongest evidence to support it?
A. Bipolar disorder
B. Alcohol withdrawal syndrome
C. Pain syndromes

4. Which of trazodone’s off-label uses has the strongest evidence to support it?
A. Little evidence is available to support the use of trazodone in any of its purported off-label uses.
B. The best evidence supports its use in chronic insomnia, with more than 15 RCTs indicating it is effective.
C. A surprise finding has been that it is effective for behavioral issues in kids who have ADHD; it may help adults, too.

5. Which if the following links gabapentin and trazodone to a most common adverse effect?
A. Gabapentin = dose-dependent CNS and respiratory depression; trazodone = nausea/vomiting, xerostomia, dizziness, drowsiness
B. Gabapentin = dose-dependent CNS priapism and suicidal ideation; trazodone = hypersensitivity reactions and peripheral edema
C. Gabapentin = cardiac arrythmias and QT prolongation; trazodone = cumulative depressant effects when given with SSRIs

Indication Deviation in Women’s Health: Off-Label Drug Use from Conception to Menopause-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-040-H01-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Pharmacist Post-test

Learning Objectives
After completing this continuing education activity, pharmacists will be able to
• RECOGNIZE diverse instances of off-label drug use in women's health, spanning pre-conception to menopause
• DISCUSS risks and advantages associated with off-label drug utilization during various reproductive stages
• IDENTIFY the pharmacist's role in advocating for safe and informed off-label drug use for women’s health

1. Which of the following can be treated through off-label use of metformin?
A. Hirsutism of PCOS
B. PCOS with BMI ≥ 25 kg/m2
C. Endometriosis

2. Which of the following medications is used off-label to induce ovulation in women experiencing infertility and trying to conceive?
A. Letrozole
B. Clomiphene citrate
C. Cetrorelix

3. Which of the following drugs is used off-label to treat menopausal hot flashes?
A. Clonidine
B. Paroxetine
C. Fezolinetant

4. Which of the following is TRUE about off-label medication use during pregnancy?
A. All drugs have sufficient efficacy and safety data to support their use during pregnancy
B. Providers should use the letter-based FDA rating system to aid in shared clinical decision-making
C. About three-quarters of pregnant women use medications for off-label uses during pregnancy

5. A patient comes to your pharmacy experiencing frequent hot flashes. She states that a friend suggested she try taking black cohosh. She takes lisinopril for hypertension and metformin for prediabetes, and she is otherwise healthy. Which of the following is the BEST response?
A. Black cohosh will interact with your blood pressure medication, so you should not take it. Ask your doctor about clonidine instead.
B. Black cohosh shows some benefit, but clinical trials are inconsistent and available data is insufficient. You can try taking 20 mg daily for a few weeks to see if your symptoms improve.
C. Black cohosh shows no benefit whatsoever for VMS of menopause. Ask your doctor about letrozole instead.

6. Which of the following is TRUE about Pregnancy Exposure Registries?
A. They steal data about women’s babies and sell it on the black market
B. They are FDA-sponsored registries that collect health information
C. Pregnant women volunteer to share their experiences with off-label drug use

Immunization: It is Now Time to Make it Unclear: Reconciling Differences between Public Health Vaccine Recommendations and FDA Product Labeling-RECORDED WEBINAR

Upon completion of this application based CE Activity, a pharmacist will be able to:

1. Compare and contrast the roles & activities of the Center for Biologics Evaluations and Research (CBER), US Food & Drug Administration (FDA), Centers for Disease Control & Prevention (CDC), and the Advisory Committee on Immunization Practices (ACIP) during the development and clinical use of vaccines in the United States.

2. Describe one specific example where the routine clinical use of a vaccine may differ from FDA-approved product prescribing information due to the following:

(a) costs, (b) disease epidemiology, (c) public acceptance, (d) vaccine supplies.

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-042-H06-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Immunizations (Aeschlimann) – Post-Test Questions

If asked, which of the following activities would the Food and Drug Administration decline to do and send to another agency?

Verify appropriate vaccine manufacturing processes
Approve advertising for vaccine products Reporting System (VAERS)
Determine the strategy for public use of vaccines in the U.S.

2.) Which of the following items would you expect to always/very-commonly see in the FDA-Approved product labeling for a vaccine product?

Instructions for preparation of the product and route of administration
Comparative effectiveness data for people taking chronic steroid therapy
Recommendations for use of lower doses in case of product shortages

3.) Which of the following is a correct example of a vaccination situation for which ACIP has issued “Shared Clinical Decision-making” (SCDM) guidance?

Intranasal influenza vaccine administration in immunocompromised persons
Respiratory syncytial virus vaccination for adults aged 60 years and older
Human papillomavirus vaccination for persons aged 16-21 years

4.) Which entity ultimately approves the content for FDA vaccine product labeling?

The Vaccines and Related Biological Products Advisory Committee
The Center for Biologic Evaluation & Research
The Center for Drug Evaluation and Research

5.) Which of the following people would be allowed to sit in the CDC’s Advisory Committee on Immunization Practices (ACIP)?

A member of a vaccine manufacturer’s current Board of Directors
A college professor whose expertise is mechanical engineering
A practicing physician who is an expert in virology and vaccine safety

6.) What does ACIP recommend after healthcare providers receive a full series of hepatitis B immunizations?

Serologic testing for all healthcare providers at high risk for occupational percutaneous or mucosal exposure to blood or body fluids.
Serologic testing for immunocomproised healthcare providers at high risk for occupational percutaneous of any type.
Molecular testing for all healthcare providers at high risk for occupational percutaneous or mucosal exposure to blood or body fluids.

TOP 10 Cardiovascular Drugs Used Off Label!!!-RECORDED WEBINAR

Upon completion of this application based CE Activity, a pharmacist will be able to:

Identify how an FDA approved and off label indication differ and the implications of that differential designation

Identify which 10 FDA approved cardiovascular drugs have the most promising off label uses for treating other cardiac or noncardiac disorders

Describe the mechanisms of action for the purported off label uses of these drugs

Identify which national guidelines or consensus statements recommend the off-label use of drugs

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-039-H01-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

Post Test “TOP 10 Cardiovascular Drugs Used Off Label!!!”

1. Which of the following drugs has been used to enhance the chances of delivering a baby in patients with Factor 5 Leiden and what is the mechanism of benefit?
a) Thiazide diuretics; reduced placental calcium that stops crystalline umbilical cord blockage
b) LMWH; preventing placental thrombosis in patients who are hypercoagulable
c) Disopyramide – decreasing the inotropic effect in hypertrophic cardiomyopathy that leads to placental detachment

2. Which of the following drugs is effective for treating anal fissures and what is the mechanism of action?
a) IV iron; iron deficiency anemia promotes fissure formation so treating it reverses fissure
b) Amiodarone; overactive potassium channels in the anus lead to apoptosis of anal mucosal cells
c) CCBs; Blood vessel dilation enhancing blood flow to targeted areas in the body

3. Which of the following drugs is properly linked to the off-label indication it is commonly used for?
a) Beta-blockers – Raynaud’s phenomenon
b) Prazosin – Nightmares in PTSD patients
c) Clonidine – Stage fright

4. Which of the following drugs is used off label for the treatment of abnormal face and body hair growth in patients and what is the mechanism of action?
a) Spironolactone – blocking the effects of testosterone in several ways
b) Beta-blockers – blocking epinephrine induced follicular stimulation
c) Clonidine – central outflow of norepinephrine causes abnormal hair growth

5. Sally Sue has had atrial fibrillation for several months. Her cardiologist has prescribed several therapies that have been ineffective, and one that is on the drug shortage list and hard to find. Which of the following might the cardiologist use off-label according to the AHA/ACC Guideline?

a) Calcium channel blockers
b) Prazocin
c) Amiodarone

The ABCD of Off-Label Medications for Weight Management-RECORDED WEBINAR

The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

Pharmacists and Pharmacy Technicians are eligible to participate in this application-based activity and will receive up to 1.0 CE Hours (or 0.1 CEUs) for completing the activity ACPE UAN 0009-0000-23-038-H01-P, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the CPE Monitor online system and your participation will be recorded with CPE Monitor within 72 hours of submission.

The ABCD of Off-Label Medications for Weight Management
Post Test
1. When working with a patient to manage ABCD, what is the first goal?

A. prevent weight regain
B. stop further weight gain
C. achieve weight reduction

2. Which of the following is the correct order of weight reduction efficacy (highest to lowest)?

A. tirzepatide > semaglutide > phentermine
B. semaglutide > SGLT2 inhibitors > phentermine
C. metformin = semaglutide > topiramate

3. What did the SELECT RCT report about patients 45 years and older with ABCD and existing cardiovascular disease who did not have diabetes?

A. The placebo-subtracted weight reduction for weekly semaglutide 2.4 mg was 15% of baseline body weight.
B. Subcutaneous semaglutide 2.4 mg once weekly reduced major adverse cardiovascular events in ABCD.
C. Subcutaneous semaglutide 2.4 mg once weekly significantly reduced weight but did not prevent cardiovascular events.

4. What is the most common adverse reaction for GLP-1 receptor agonist-based medications?

A. nausea and other gastrointestinal adverse effects
B. hypoglycemia
C. sleep disturbance

5. With which drug class can tirzepatide interact ?

A. beta blockers
B. ACE inhibitors
C. oral hormonal contraceptives

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