INTRODUCTION

The number of older adults (aged 65 years and older) is expected to exceed 1.5 billion by 2050.¹ Multimorbidity is expected to affect 65% of older adults aged 65 to 84 years and up to 82% of those aged 85 years or older.¹ With multimorbidity, the number of medications taken by the vulnerable older adult population increases. Along with drug-disease and drug-drug interactions, age-related physiological changes that alter pharmacokinetics and pharmacodynamics increase the risk of adverse drug events (ADEs).²

 

Throughout this continuing education activity, consider a hypothetical patient, Ms. Polly, who is an 85-year-old female. Enrolled in a Program of All-Inclusive Care for the Elderly (PACE), she has been able to live safely at home. Table 1 lists her current medication regimen.

 

Table 1. Medication Regimen

Acetaminophen/diphenhydramine PM 25/500 mg, 2 tablets nightly PRN for insomnia Alendronate 70 mg weekly for osteoporosis Amlodipine 10 mg daily for hypertension Aspirin 81 mg daily for heart attack prevention Cetirizine 10 mg daily for allergies Donepezil 10 mg daily for Alzheimer’s disease Fluticasone nasal spray 2 sprays in each nostril daily for allergies Furosemide 20 mg daily for peripheral edema Gabapentin 300 mg twice daily for neuropathic pain Glipizide ER 5 mg daily for pre-diabetes Ibuprofen 200 mg three times daily for pain Omega-3 Fish Oil 1000 mg twice daily for hyperlipidemia Oxybutynin 5 mg twice daily for overactive bladder Pantoprazole 40 mg daily for GERD Paroxetine 30 mg daily for depression Potassium chloride 10 mEq daily for potassium deficiency Pravastatin 40 mg daily for hyperlipidemia Propranolol 40 mg twice daily for hypertension Senna-docusate 8.6-50 mg, 2 tablets daily for constipation

ABBREVIATIONS: GERD = gastroesophageal reflux disease; mEq = milliequivalent; mg = milligrams; PRN = as needed

 

Ms. Polly’s healthcare needs have become more complex with her increasing confusion, declining ability to perform activities of daily living, and a recent fall. Her daughter continues to be her main caregiver and has requested more help from PACE; thus, the prescriber has reached out to the clinical pharmacist for assistance. This CE activity will review best practices for deprescribing with a focus on why, who, when, what, and how to safely deprescribe medications in the vulnerable older adult population.

 

WHY, WHO, AND WHEN TO DEPRESCRIBE

 

WHY: Older Adults Have Specific Needs

Since older adults have differing health and functional statuses, prescribers must individualize medication selection for these patients. Prescribing the right medication and dose for the right indication at the right time while providing benefit and avoiding ADEs is challenging. Comorbidities and complexity of medication regimens may result in suboptimal medication use. Suboptimal medication use comprises (1) underprescribing, (2) polypharmacy or overuse, and (3) high-risk prescribing, such as potentially inappropriate medications (PIMs), prescribing cascades, and anticholinergic and sedative effects.²

 

Estimates suggest that as many as 65% of older adults in the United States are exposed to polypharmacy and 29% to PIMs.^3,4 Polypharmacy is generally defined as the use of five or more medications and often occurs because of a prescribing cascade, which means the culprit medication causes an ADE that is mistaken for a new medical condition for which a subsequent medication is initiated as treatment. “Hyperpolypharmacy” or “excessive polypharmacy” is generally considered the use of 10 or more medications.⁵ Polypharmacy is associated with undesirable outcomes: frailty, cognitive decline, functional decline, falls, fractures, emergency department (ED) visits, hospitalizations, and mortality.^3,5,6

 

Evidence suggests that older age and indicators of poor health (i.e., multiple chronic conditions, cognitive decline, frailty) are risk factors for polypharmacy. The number of medications in a patient’s regimen may be the single most important predictor of ADEs.⁶ The likelihood of taking inappropriate medication increases with the number of drugs prescribed. Experts consider medications inappropriate in older adults when they pose individual or cumulative adverse event risk.

 

The Choosing Wisely Campaign brought awareness and encouraged conversations between healthcare providers and patients about medication overuse and potentially doing more harm than good within healthcare. This partnership between the American Board of Internal Medicine (ABIM) Foundation and specialty societies was formed in 2012. At the time, the healthcare field and society generally thought that more care was better, and patients tended to perceive prescribers as ignoring their patients’ interests if they did not prescribe certain medications.⁷

 

Understanding suboptimal prescribing allows healthcare providers to mitigate the risk of poor health outcomes in vulnerable older adults. Deprescribing is the process of healthcare professional-supervised medication withdrawal with the goal of managing polypharmacy and improving outcomes.⁸ Pharmacists review medication regimens comprehensively to identify and consider discontinuation of high-risk medications and those that cause more harm than benefit. Deprescribing encourages a proactive and systematic approach to mitigate potential medication-related problems (MRPs). This approach is preferable over a reactive approach (i.e., discontinuing an offending medication after an ADE occurs).

 

PAUSE AND PONDER: Why should healthcare providers re-evaluate medications periodically?

 

According to the World Health Organization, the global ADE-related mortality rate increased approximately 3.3-fold from 2001 to 2019, with the highest rates occurring in those aged 75 years and older.⁹ A systematic review of 14 hospital-based observational studies in older adults found an ADE to occur more often with an increased number of medications.¹⁰ More than 50% of ADEs could be prevented with safe prescribing practices.⁵ Safe medication use requires that healthcare providers ensure regimen appropriateness, considering treatment initiation, treatment optimization, and cessation of unnecessary or inappropriate medications.

 

WHO: The Age-Friendly Movement

The Institute for Healthcare Improvement in partnership with The John A. Hartford Foundation, American Hospital Association, and the Catholic Health Association developed the Age-Friendly Health Systems initiative to improve the care of older adults and the lives of caregivers. This framework—the Age-Friendly 4Ms, depicted in Figure 1—is a patient-centered approach to medication optimization that addresses polypharmacy and deprescribing. Conversations with healthcare providers can be re-framed to discuss “What Matters” to the patients and caregivers. Medications impact all the “M” domains: What Matters, Mentation and Mobility.^11,12

 

Figure 1. Age-Friendly Health Systems 4Ms Framework¹¹

 

Reasons for deprescribing may vary from patient to patient. When reviewing common goals for deprescribing, consider the perspectives of the patient, the caregiver, and the healthcare team. Identify which reasons for deprescribing may be most relevant or meaningful to each party involved in the patient’s care. Examples include

• reducing medication regimen complexity and pill burden to improve adherence
• reducing anticholinergic burden to improve and/or preserve cognitive function
• reducing fall and fracture risk
• reducing hospitalizations
• reducing mortality
• reducing costs

 

These deprescribing goals improve patients’ quality of life. Deprescribing considers not only single medications but also the aggregate interaction risk from multiple medications.¹³

 

Deprescribing often presents challenges due to barriers faced by healthcare providers and patients. Healthcare providers’ may have limited time and lack of training which serves as the most significant barriers. Patient-related barriers to deprescribing include satisfaction with medications, reluctance, resistance to change, and opposition to alternative treatments. Despite these challenges, many barriers can be addressed through education, communication, and shared decision-making.

 

Although many patients express not wanting to take medications, their beliefs and acceptance of polypharmacy and discontinuing medications is poorly understood. To further understand patients’ views, preferences and willingness, researchers from the University of South Australia and University of Sydney developed the Patients’ Attitudes Towards Deprescribing (PATD) questionnaires, including the revised PATD for older adults and caregivers and the revised PATD for cognitively impaired individuals (rPATDcog).^14-16

 

A population-based survey of Medicare beneficiaries 65 years and older using PATD questions found most older adults are open to having one or more medications deprescribed and two-thirds want to reduce the number of medications taken.¹⁷ A multi-center cross-sectional survey found older adults and caregivers are open to deprescribing, with more than 90% willing to discontinue a medication if a healthcare provider initiates the conversation.¹⁸

 

While primarily used for research, providers may use the revised PATD questionnaire clinically to target patients and caregivers who are willing to discontinue medications. The original work is available here: https://www.australiandeprescribingnetwork.com.au/925-2/.¹⁶ Understanding attitudes and willingness may enhance shared decision-making conversations about deprescribing.

 

PAUSE AND PONDER: How do you determine which medications to deprescribe?

 

WHEN TO DEPRESCRIBE

Older adults are often high-risk for potential MRPs due to pharmacokinetic (the body’s effect on a medication) and pharmacodynamic (a medication’s effect on the body) changes. However, advanced age is not an independent risk factor for MRPs. Elements of high-risk patients who may benefit from deprescribing include the following¹⁹:

• Polypharmacy: Use of multiple medications is the strongest risk factor for MRPs. Table 2 lists common types of potential MRPs.
• Multimorbidity: Having multiple chronic conditions increases the risk of drug-disease interactions.
• Renal impairment: Reduced renal function increases ADE risk.
• Transitions of care: Medication management by multiple prescribers can result in miscommunication and medication discrepancies, such as inadvertent continuation.
• Nonadherence: Patients may be nonadherent to their medication regimens due to experiencing real or perceived adverse effects and/or lack of benefit, complexity, burden, and cost.
• Limited life expectancy/end of life care: Goals of care change from slowing disease progression and prolonging life to improving quality of life. Patients may no longer benefit from preventive medications and use certain medications for symptomatic management.
• Frailty and dementia: Frailty—an age-related syndrome of physiologic decline—is associated with increased adverse events and risk of harm, such as falls, which can be detrimental. ADEs may worsen or exacerbate these syndromes (i.e., fatigue or cognitive impairment).

 

Table 2. Types of Potential Medication-Related Problems

Adverse Drug Events Adverse Drug Interactions Excessive Duration Inappropriate/Unnecessary Medications Ineffective Therapy No Indication Nonadherence Suboptimal Dosing Supratherapeutic Dosing

 

 

Aging is not an identical experience for every person, so frailty—declining mental and physical resilience, or the ability to bounce back and recover from events like illness and injury—is a more appropriate measure of health status than age alone. Frailty has been associated with poor patient outcomes. The Edmonton Frail Scale is a validated, reliable, and multidimensional screening tool for all healthcare settings. The free tool with a training course is available here: https://edmontonfrailscale.org/. It assesses nine domains: cognition, general health status, functional independence, social support, medication use, nutrition, mood, continence, and functional performance. The highest level of frailty is a score of 17.²⁰ Assessing frailty severity can help with shared decision-making and determining goals of care.

 

PAUSE AND PONDER: How can you use prescribing clinical tools for deprescribing?

 

WHAT TO DEPRESCRIBE

While few studies have measured the clinical implications of underprescribing, evidence has shown an association between polypharmacy and PIMs. A systematic review of 38 clinical trials found that deprescribing interventions in community-dwelling older adults (aged 65 years and older) may provide small reductions in use of PIMs and mortality.⁶ Prescribers and pharmacists should periodically reevaluate any medication initially prescribed for a clinical indication since benefits, risks, conditions, and comorbidities change over time, which may result in inappropriate use. Medication review should consider the following factors: goals of care, remaining life expectancy, treatment targets, time until benefit, number needed to treat (NNT, a statistical measure that indicates how many patients need to be treated with a specific intervention to prevent one additional adverse outcome), number needed to harm, and ADEs.²¹

 

Collaborative approaches and numerous clinical application tools highlighted below are available for safe prescribing and to reduce medication overuse. Focusing on medications and potential ADE risk, healthcare providers can employ these clinical tools to identify medications for potential deprescribing.

 

Risk-Benefit Analysis

Older adults are vulnerable to ADEs associated with “high-risk” single medications and medication classes, including anticoagulants, benzodiazepines, cardiovascular agents, digoxin, hypoglycemics, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, psychotropics, and those with anticholinergic effects. “High-risk” medication combinations—for example, angiotensin-converting enzyme inhibitors, diuretics, and NSAIDs in patients with chronic kidney disease (known as the “triple whammy”)—augment ADE risk.¹³

 

In a “Less is More” special communication about polypharmacy and deprescribing, experts proposed grouping medications into two categories for older adults to determine if the likely benefit outweighs potential risk/harm, while noting that medications may fall into both categories.¹³

 

“Disease and/or symptom control medications” are used to manage active disease and symptoms and help maintain quality of life.¹³ Discontinuing these medications could result in symptom return or functional decline due to disease worsening. Examples include analgesics, anti-anginals, anti-heart failure medications, and levothyroxine. Dose reduction of disease/symptom control drugs may be appropriate if symptoms are mild or intermittent, but these should be discontinued if altogether ineffective. Notably, aggressive treatment may be inappropriate for hypertension or diabetes management in some older adults, as this could increase the risks of hypotension or hypoglycemia, respectively.¹³

 

Preventive medications are intended to prevent future morbid events.¹³ Their use should be guided by assessment of absolute risks and benefits of treatment for individual patients, taking into consideration the time required for benefit (known as "time to benefit"), patient preferences, and estimated life expectancy. For example, osteoporosis guidelines recommend a “drug holiday” (temporary discontinuation of therapy) from bisphosphonates depending on fracture risk after five years of treatment to mitigate risk of atypical femoral fractures and osteonecrosis of the jaw. Despite discontinuation, bisphosphonates’ anti-fracture effects persist because this medication class has long half-lives and remain stored in bone for up to 10 years. Another example is statins, which are commonly used for primary prevention of cardiovascular events. Evidence suggests that statin discontinuation after eight years does not increase cardiovascular event risk.¹³

 

Choosing Wisely Campaign

The American Board of Internal Medicine’s global Choosing Wisely (CW) Campaign encourages patient engagement and healthcare provider conversation to choose care that is evidence-based, necessary, and free from harm. Since 2012, a compilation of more than 600 evidence-based statements from approximately 80 healthcare organizations advise healthcare providers, patients, and caregivers about optimization, appropriateness, and avoidance of unnecessary medical testing and treatments, available at https://www.choosingwisely.org/.^7,22,23,24

 

The American Society of Consultant Pharmacists (ASCP) convened a task force in 2018 under the CW campaign to further help pharmacists initiate and implement deprescribing. The task force reinforced deprescribing in older adults by reviewing and providing evidence-based references. ASCP’s guidance provides ten statements focused on avoiding DDIs and prescribing cascades and encouraged medication reviews to mitigate potential ADEs²⁵:

1. DO NOT initiate medications to treat new and emerging symptoms without first ascertaining that the new symptom is not an ADE related to an already prescribed medication.
2. DO NOT continue medications at care transitions without reviewing and reconciling to verify accurate and complete medication lists in concert with current medical problems.
3. DO NOT recommend highly anticholinergic medications in older adults without first considering safer alternatives or non-pharmacologic measures.
4. DO NOT use anticholinergics concomitantly with cholinesterase inhibitors for dementia.
5. DO NOT use two or more medications known to increase bleeding risk (e.g., antiplatelets, direct oral anticoagulants [DOACs], warfarin, aspirin, NSAIDs, corticosteroids, selective serotonin reuptake inhibitors), without evaluating the potential risks and benefits.
6. DO NOT prescribe or routinely continue medications for older adults with limited life expectancy without consideration to individual goals of care, presence of comorbidities, and time to benefit for preventive medications.
7. DO NOT use three or more central nervous system-active medications (e.g., antidepressants, antipsychotics, benzodiazepines, antiepileptics, Z-drugs, opioids, gabapentinoids).
8. DO NOT combine opioids with benzodiazepines or gabapentinoids to treat pain and DO re-evaluate routinely for deprescribing during chronic use.
9. DO NOT prescribe tramadol without consideration of the potential risks and harms related to serotonergic excess, seizures, falls, and drug-drug interactions (DDIs).
10. DO NOT use strong CYP3A4 and P-glycoprotein inhibitors or inducers with DOACs and DO periodically assess for such DDIs.

 

The American Geriatrics Society (AGS) also worked on the CW campaign to identify treatments that potentially have more risks than benefits in older adults, concluding the following²⁶:

• DO NOT use antipsychotics first-line to treat behavioral and psychological symptoms of dementia.
• DO NOT use benzodiazepines or sedative-hypnotics first-line for insomnia, agitation, or delirium.
• DO NOT use cholinesterase inhibitors for dementia without periodic assessment for perceived cognitive benefits and adverse gastrointestinal effects.
• DO NOT use antidiabetics to achieve hemoglobin A1c less than 7.5% in most older adults; moderate control is generally better.
• DO NOT use antimicrobials to treat bacteriuria in older adults unless they experience specific urinary tract symptoms.
• DO NOT maintain long-term proton pump inhibitor (PPI) therapy for gastrointestinal symptoms without an attempt to stop or reduce PPI at least once per year in most patients.
• DO NOT use NSAIDs for patients with hypertension, heart failure, or chronic kidney disease.
• DO NOT use prescription appetite stimulants or high-calorie supplements for treatment of anorexia or cachexia (unexplained wasting) in older adults.
• DO NOT prescribe medication without conducting a medication regimen review.

 

Prescribing Cascades

It bears repeating that providers should not initiate medications—prescription or over-the-counter (OTC)—or use a new medical device to treat new and emerging symptoms without first ascertaining that the new symptom is not an ADE of an already prescribed medication.²⁴ This is the first CW statement endorsed by ASCP and it describes a prescribing cascade. Prescribing cascades are preventable, yet often unrecognized, even though researchers in the geriatric field first introduced the concept in the 1990s and then revisited and expanded upon it in 2017.^27,28 They emphasized that “the identification and interruption of prescribing cascades is an important, actionable, and underappreciated opportunity to improve medication safety in older people.”^27,28

 

Prescribing cascades contribute to polypharmacy and adverse outcomes in vulnerable older adults. By becoming familiar with the common prescribing cascades, outlined in Table 3, pharmacists and pharmacy technicians can identify culprit and cascade medications. If culprit medications remain clinically indicated, prescribers should use the lowest possible dose, a safer alternative with fewer adverse effects, or non-pharmacologic therapy, rather than initiating a cascade medication to address the ADE.

Table 3. Prescribing Cascades to Avoid or Amend29
CULPRIT MEDICATION	ADVERSE DRUG EVENT	CASCADE MEDICATION
ACE inhibitors	Cough	Cough suppressants
Alpha-1 blockers	Orthostatic hypotension	Meclizine
Amiodarone	Tremor	Lithium
	Hypothyroidism	Thyroid hormones
Amitriptyline	Cognitive impairment	Cholinesterase inhibitors
Antipsychotics	Cognitive impairment	Cholinesterase inhibitors
	Extrapyramidal symptoms	Benztropine
Benzodiazepines	Cognitive impairment	Cholinesterase inhibitors
Beta blockers	Depression	Antidepressants
Bisphosphonates	GERD	PPIs/H2RAs
Bupropion	Insomnia	Sedatives-hypnotics
Calcium channel blockers	Constipation	Laxatives
	Peripheral edema	Diuretics
Cholinesterase inhibitors	Insomnia	Sedatives-hypnotics
	Urinary incontinence	OAB anticholinergics
Corticosteroids	Insomnia	Sedatives-hypnotics
Diuretics	Urinary incontinence	OAB anticholinergics
Dopaminergics	Psychotic symptoms	Antipsychotics
Gabapentinoids	Peripheral edema	Diuretics
Lithium	Extrapyramidal symptoms	Antiparkinsonians
	Tremor	Propranolol
Metoclopramide	Extrapyramidal symptoms	Antiparkinsonians
NSAIDs	GI bleeding or heartburn	PPIs/H2RAs
	Hypertension	Antihypertensives
OAB anticholinergics	Cognitive impairment	Cholinesterase inhibitors
SGLT2 inhibitors	Urinary tract infections	Antibiotics
SSRIs/SNRIs	Insomnia	Sedatives-hypnotics
Statins	Myalgia	NSAIDs/opioids
Thiazide diuretics	Hyperuricemia or gout	Allopurinol/colchicine

ABBREVIATIONS: GERD = Gastroesophageal reflux disease; GI = Gastrointestinal; H2RAs = Histamine-2 receptor antagonists; NSAIDs = Non-steroidal anti-inflammatory drugs; OAB = Overactive bladder; PPIs = Proton pump inhibitors; SGLT2 = Sodium glucose cotransporter-2; SNRIs = Serotonin norepinephrine reuptake inhibitors; SSRIs = Selective serotonin reuptake inhibitors

 

Anticholinergic Medications

Older adults are more sensitive to anticholinergic adverse effects, including confusion, dry mouth, blurry vision, constipation, and urinary retention. A large case-control observational study of 58,769 patients diagnosed with dementia and 225,574 matched controls found statistically significant associations of dementia risk with exposure to anticholinergic medications, such as antidepressants, antipsychotics, antiparkinsonians, antiepileptics, and bladder anticholinergics.³⁰ Participants who took a single strong anticholinergic medication daily for three years had almost 50% increased odds of dementia within a 10-year period. Dementia risk was increased in patients taking more than one anticholinergic medication due to the cumulative impact.³⁰ Pharmacists can use one or a combination of multiple validated expert anticholinergic scales to calculate aggregate anticholinergic scores. An anticholinergic burden score of three or higher is associated with increased cognitive impairment and mortality. The most frequently validated scale is the Anticholinergic Cognitive Burden (ACB) scale.^31,32 An Anticholinergic Burden Calculator is available at no cost for use here: https://www.acbcalc.com/.

 

A small longitudinal study of 69 participants found those who took an anticholinergic medication in combination with the cholinesterase inhibitor donepezil over a two year period declined by seven points on the Mini-Mental State Examination as compared with a three point decline in those taking donepezil alone.³³ Thus, concomitant therapy with anticholinergics may counteract efficacy of cholinesterase therapy, resulting in a more rapid cognitive and functional decline.

 

Revisiting the case, Ms. Polly is taking donepezil for Alzheimer’s disease. Her prescriber consults with the pharmacist to initiate memantine for her progressive dementia due to increasing confusion and declining function. Medication review identifies several medications with anticholinergic effects that may be worsening Ms. Polly’s cognitive function, including cetirizine, diphenhydramine, furosemide, oxybutynin, and paroxetine. The pharmacist recommends deprescribing anticholinergic medications for which risk outweighs benefit. With reducing aggregate anticholinergic burden, donepezil may be more effective. This avoids added polypharmacy by initiating memantine, effectively preventing a prescribing cascade. Following discontinuation of these medications, the pharmacy technician can follow up with Ms. Polly and her caregiver to assess if there has been improvement.

 

Resources are available to assess polypharmacy and identify PIMs in vulnerable, older adults. The following section provides an overview, applicability, and utility in practice for the most common clinical tools: Beers Criteria, STOPP/START Criteria, STOPPFall Criteria, STOPPFrail Criteria, and the Medication Appropriateness Index.

 

Beers Criteria

The late Mark Beers, MD and his colleagues developed the Beers Criteria in 1991 with a mission to identify medications for which potential harm outweighed expected benefit and that should be avoided in long-term facilities. Since then, several updates have expanded the criteria to apply to older adults aged 65 years and older in ambulatory, acute, and institutionalized care settings, except end-of-life and hospice. Upon Dr. Beers’s death, AGS assumed responsibility for maintaining the criteria.

 

The 2023 AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults is a well-known, widely available clinical tool to support shared clinical decision-making. It is available for free in the Journal of the American Geriatrics Society.³⁴ For ease of clinical practice application, the AGS provides a pocket card and an app, for a fee, available at https://geriatricscareonline.org/. To encourage engagement and conversation, AGS provides patient and caregiver educational resources that are available for free at https://www.healthinaging.org/.

 

The AGS Beers Criteria lists medications and medication classes that the society and its geriatric expert panel consider potentially inappropriate for use in older adults. The criteria are structured by category with each section including a clear rationale and recommendation:

1. Medications considered potentially inappropriate
2. Medications potentially inappropriate in patients with certain diseases or syndromes
3. Medications to use with caution
4. Potentially inappropriate drug-drug interactions
5. Medications to avoid or adjust dosages based on renal function
6. Medications with strong anticholinergic effects

 

Importantly, the identified medications are “potentially inappropriate” rather than “definitely inappropriate.” The key word is “potentially,” as the prescribing and deprescribing processes are to be patient centric. The AGS panel recognizes that harm is typically more pronounced in the “old-old” than in the “young-old” and in patients with complex multi-morbidity and frailty.³⁴ The indicators are categorized based on whether they involve avoiding the initiation of a PIM or discontinuing one that is already prescribed. To apply the AGS Beers Criteria, prescribers and pharmacists must identify the PIMs and, when clinically appropriate, consider safer pharmacologic or nonpharmacologic alternatives.

 

STOPP/START Criteria

The Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) criteria are additional resources for identifying potentially inappropriate prescribing in older adults. These aim to identify PIMs and potential prescribing omissions, respectively.³⁵ The STOPP criteria are most helpful in the context of polypharmacy. The original version, published in 2008, included 65 STOPP criteria, which more than doubled in the third version, updated in 2023, with 133 STOPP criteria. These more expansive criteria assist pharmacists and pharmacy technicians in identifying and preventing more DDIs, drug-disease interactions, and potential ADEs during medication reviews.

 

The STOPP criteria is divided into sections by organ systems—including cardiovascular, coagulation, central nervous, renal, gastrointestinal, respiratory, musculoskeletal, urogenital, and endocrine—with separate sections for drugs that increase fall risk, analgesics, and antimuscarinic or anticholinergic drugs.³⁵ The criteria also address the need to clarify an indication for each medication, labeling the following as PIMs:

• Any medication prescribed without a clinical indication
• Any medication prescribed beyond recommended duration
• Any duplicate medication class

 

Additional variations of the STOPP criteria help healthcare providers to identify PIMs in older adults with a high risk of falls (STOPPFall) and in those with limited life expectancy (STOPPFrail).^36,37 STOPPFall identifies medication classes considered to be fall-risk-increasing-drugs (FRIDs). To further assist in shared-decision making of deprescribing, practical decision trees based on the STOPPFall guidance are available online (https://kik.amc.nl/falls/decision-tree/).³⁶

 

While most prescribing tools are designed to identify and prevent PIMs in the general older population, STOPPFrail consists of 27 potentially inappropriate prescribing indicators to assist healthcare providers in deprescribing in frail older adults.³⁷ Deprescribing in frail older adults may improve their quality of life through a reduction in adverse events, hospitalizations, and mortality. Medication review in this population should focus on deprescribing and symptom management, rather than preventive and intensive treatment. STOPPFrail is applicable in adults aged 65 or older who meet all the following criteria³⁷:

• End-stage irreversible pathology
• Poor one year survival prognosis
• Severe functional or cognitive impairment or both
• Symptom control is priority rather than preventing disease progression

 

Example criteria include³⁷

• Avoid antiplatelets for primary cardiovascular prevention due to lack of evidence
• Bisphosphonates are unlikely to be beneficial for short-term osteoporosis treatment
• Aim for antidiabetic monotherapy with less stringent glycemic control (i.e., hemoglobin A1c goal of less than 8%)

 

End-of-Life Care

Prescribers and pharmacists should re-evaluate medications and minimize the pill burden for patients receiving palliative care, particularly at end-of-life (i.e., life expectancy of less than three months). Prevention of long-term complications is no longer indicated.²¹ Rather, the goal is comfort care through symptom-specific medications (SSMs) to treat pain, dyspnea (shortness of breath), nausea, cognitive disturbances, anxiety, and depression. The number of SSMs increases while the number of medications intended to treat comorbidities decreases. Therefore, the definition of polypharmacy shifts for end-of-life care, focusing on inappropriate medication use.

 

The shared decision-making process must still consider patient and caregiver preferences. While some patients may prefer only symptomatic treatment without life-prolonging measures, other patients may feel neglected following discontinuation of certain long-term medications.²¹ A literature review of 67 articles established preliminary recommendations for long-term medication classes shown in Table 4.²¹

 

Table 4. Deprescribing at End-of-Life21
MEDICATION CLASS	RECOMMENDED ACTION PLAN	GDR
Anticoagulants	Discontinue for deep vein thrombosis primary prevention	No
Antihyperglycemics	Reduced dosages to prevent hypoglycemia	Variable
Antihypertensives	Discontinue for hypertension	Yes
Antimicrobials	Variable: goal is symptom control	No
Statins	Discontinue	No

ABBREVIATIONS: GDR = gradual dose reduction

 

Medication Appropriateness Index

Unlike the previously mentioned clinical tools that are PIMs and medication class lists developed by expert consensus; the Medication Appropriateness Index (MAI) is patient centric. The MAI, developed more than 30 years ago, is a patient screening tool that measures potentially inappropriate prescribing in older adults. The 10 simple questions focus on indication, effectiveness, dosing, duration, and potential for interactions to ultimately rate medications as appropriate, marginally appropriate, or inappropriate.^38,39 A MAI Calculator is available at no cost for use here: https://globalrph.com/medcalcs/medication-appropriateness-index-calculator/.

 

HOW TO SAFELY DEPRESCRIBE

 

Deprescribing Tools

Once polypharmacy and PIMs are identified, many clinical tools are available to analyze benefit versus risk and guide pharmacy teams on how to safely discontinue specific medications and medication classes.

 

Deprescribing.org

https://deprescribing.org/resources/

Canadian Medication Appropriateness and Deprescribing Network

https://www.deprescribingnetwork.ca/professionals

 

Deprescribing.org is a website developed by Canadian pharmacists that provides guidance, tools, and approaches for deprescribing.⁴⁰ Included within these resources are evidence-based guidelines and easy to use algorithms to determine when and how to stop specific medication classes: antihyperglycemics, antipsychotics, benzodiazepines, cholinesterase inhibitors, memantine, and PPIs.⁴⁰ The companion site, Canadian Medication Appropriateness and Deprescribing Network, provides additional guidance on commonly inappropriate medications for healthcare providers and patients, including a Deprescribing Educational Program and brochures.⁴¹

 

US Deprescribing Research Network https://deprescribingresearch.org/resources-2/resources-for-clinicians/

The US Deprescribing Research Network is a tool funded by the National Institute of Aging to develop and provide information on deprescribing for older adults.⁴² The network’s efforts center around four “cores” addressing the needs of different stakeholders (e.g., researchers, patients) and a series of working groups focusing on research and standardized outcome measures. Resources for healthcare providers promote education by providing guides for specific medication classes and reference the deprescribing tools described above.⁴²

 

Primary Health Tasmania https://www.primaryhealthtas.com.au/resources/deprescribing-resources/

Primary Health Tasmania is a not-for-profit organization in Australia that provides a comprehensive guide to personalized deprescribing, including principles, assessment of benefit versus harm, and patient and healthcare provider perceptions. These in-depth guidelines recommend deprescribing strategies for an extensive list of common medication classes: allopurinol, anticholinergics, anticoagulants, antiepileptics, antihyperglycemics, antihypertensives, antiplatelets, antipsychotics, benzodiazepines, bisphosphonates, cholinesterase inhibitors, gabapentinoids, glaucoma ophthalmics, inhaled corticosteroids, long-acting nitrates, NSAIDs, opioids, PPIs, statins, and calcium and vitamin D.⁴³

 

MedStopper https://medstopper.com/

MedStopper is an online clinical tool for polypharmacy that assists healthcare providers, patients, and caregivers in the shared decision-making process and prioritization of deprescribing.⁴⁴ Upon entering a patient’s regimen, MedStopper arranges the medications from “more likely to stop” to “less likely to stop,” based on the criteria in Table 5. A team of clinicians and researchers affiliated with Canadian healthcare institutions, including the University of British Columbia and the Centre for Effective Practice developed this site and is grounded in evidence-based resources such as the Beers and STOPP/START Criteria. However, it remains in the Beta testing phase, so pharmacy teams should still use it with caution.⁴⁴

 

Table 5. Deprescribing Opportunities and Prioritization44
Medication	Conversation
Potential to improve symptoms	Is the medication helping symptoms?
Potential to reduce the risk of future illness	Does the effectiveness justify the potential adverse effects, inconvenience, and cost?
Likelihood to cause harm	Are symptoms caused by medications?

 

Using the Edmonton Frail Scale, healthcare providers can identify patients as frail to adjust MedStopper’s “may cause harm” ranking. The specific indication for each medication affects the ranking categories for “may improve symptoms” or “may reduce future illness.” Categories are based on the rating levels of an unhappy, neutral, or happy face, with a color-coded discontinuation priority. Medications and indications also include links for resources, such as calculators for risk/benefit assessment, NNT, Beers Criteria, or STOPP Criteria. Healthcare providers can reference the tapering suggestions and symptom monitoring, as appropriate.⁴⁴

 

Go back and review Ms. Polly’s medication regimen in Table 1. Which medications may be inappropriate based on the numerous prescribing and deprescribing tools that are readily available? Figure 2 shows a snapshot of a suggested plan for deprescribing utilizing the MedStopper clinical tool.

 

Figure 2. Deprescribing Plan Based on Stopping Priority by MedStopper

NOTE: Incomplete medication regimen

 

PAUSE AND PONDER: When do medications need a gradual dose reduction for discontinuation?

 

Pharmacist-Led Deprescribing

Research shows that comprehensive medication reviews may reduce PIM use and mortality in community-dwelling older adults aged 65 years and older.⁶ A narrative review of 25 global randomized controlled trials found that pharmacist-led deprescribing interventions had a beneficial effect on 69% of medication outcomes—including discontinuation, dose reductions, and medication changes—for patients with a mean age of 60 years or older residing in the community and nursing facilities.⁴⁵

 

Pharmacists must follow a stepwise, patient-centric approach to deprescribing, while performing a comprehensive medication review of prescription and OTC medications as depicted in Figure 3. Since prescribing and deprescribing clinical tools do not consider preferences, life expectancy, and goals of care, it is essential to understand “what matters” to the patient and/or caregiver.

 

Figure 3. Stepwise Approach to Deprescribing

ABBREVIATIONS: MRPs = medication-related problems

 

Prescribers, pharmacists, and pharmacy technicians should assess if patients are not adhering to prescribed medications and, if not, why. Opportunities to deprescribe may be identified by asking just one question to a patient and/or caregiver. Pharmacy technicians are typically trained to ask, “do you have any questions for the pharmacist about your medication?” Instead, open-ended questions, such as “how do you feel about the number and types of medication you take?” or “how did your new medication help with your symptoms?” could gather more useful information. It is also important to ask if patients experience any adverse effects from their medications.

 

What Matters and Shared Goals

Deprescribing conversations ought to involve shared decision-making. Research shows older adults’ priorities are typically maintaining cognition, function, and independence over life extension.^46,47 Patient preferences and health status change over time. Knowing a patient’s priorities and preferences about medication use helps align treatment decisions and guide deprescribing.

 

To determine a patient’s health priorities and preferences, healthcare providers can use the universal health Outcome Prioritization Tool (OPT) which is nonspecific to diseases and treatments. This simple tool elicits the preferences of older adults by having them consider trade-offs and rank the relative importance of four health outcomes^46,47:

1. extending life (regardless of health)
2. preserving independence/maintaining function and activities of daily living
3. reducing or eliminating pain
4. reducing or eliminating symptoms (e.g., dizziness, fatigue, nausea, shortness of breath)

 

Several studies found that preserving independence and reducing pain were the most important health outcomes, whereas life extension was the least important.^18,48,49 In the Older Patients’ Perceptions of Medicines and Willingness to Deprescribe survey, of the 50 participants, 76% wanted to keep their symptomatic medications and 61% wanted to keep their preventive medications.¹⁸

 

The “What Matters to You?” study of 350 patients used the OPT to assess the most important health outcome for older adults.⁵⁰ Patients with cognitive impairment more often prioritized life extension. Importantly, cognitively impaired patients may struggle to understand health outcomes and the “trade-off principle”—prioritizing one health outcome while accepting potential deterioration in other health outcomes—which makes patients weigh and prioritize health goals. Patients with declining health status are generally more accepting of further decline. A secondary outcome found that the OPT is feasible for intensive treatment decision-making. For those patients who are unable to prioritize the four health outcomes, the OPT is still useful to facilitate a conversation about patient preferences and trade-offs to align decision-making.⁵⁰

 

Considering Ms. Polly: how can the 4Ms aid in recommending oxybutynin discontinuation to her prescriber? “What matters to the patient is being able to continue to live in her home. Oxybutynin is anticholinergic and is negatively affecting her mentation and mobility as she has recent falls. Please consider a discontinuation trial of oxybutynin and non-pharmacologic options for overactive bladder.”

 

Identifying Medications for Discontinuation

Upon establishing goals of care, the next step is to engage the patient or caregiver and decide whether to deprescribe any medications. Common reasons for deprescribing include

1. No active indication (e.g., health condition resolved)
2. New or worsening condition
3. Potential risks outweigh anticipated benefits
4. Preventive indication with life-limiting conditions
5. Lack of benefit or ineffectiveness
6. Result of a prescribing cascade
7. Nonadherence
8. Interactions or ADEs

 

Prescribers and pharmacists can use the available prescribing and deprescribing clinical tools, but they must also review all medications and assess the benefit versus risk for individualized patients.

 

Developing an Action Plan

Upon identifying medications to deprescribe, prescribers and pharmacists must collaborate to develop an action plan to implement, monitor, and follow-up. When deprescribing, withdraw medications one-by-one by prioritizing those that are inappropriate and/or increase the risk of harm. It is critical to continuously consider “what matters” to the patient. Multiple medications can be withdrawn simultaneously if patients are experiencing ADEs, medications are easy to discontinue, or if they have minimal withdrawal effects.

 

If deprescribing is justified, prescribers, pharmacists, and pharmacy technicians need a plan of action for each medication (i.e., whether to abruptly stop or if gradual dose reduction (GDR) is necessary). Healthcare providers need to educate patients or caregivers on withdrawal symptoms to look for and emphasize the need to promptly report them.

 

Certain medications require a GDR or taper to prevent an adverse drug withdrawal event—meaning discontinuation results in clinically significant symptoms or signs—or worsened conditions.⁵¹ GDRs can identify the lowest effective dose, minimize symptom re-occurrence, and encourage patient willingness. For example, discontinuing benzodiazepines may cause agitation. If this withdrawal symptom is unfamiliar to healthcare providers, then a prescribing cascade may occur with initiation of an antipsychotic.⁴³

 

Most medications have limited evidence and few guidelines for deprescribing. If no guidance is available, it is safer to attempt a GDR over weeks to months to discontinue rather than abruptly discontinuing. If a deprescribing guideline is unavailable, taper and discontinue medications in reverse of guideline recommended treatment. For example, the prescribing information for donepezil recommends initiation of therapy at 5 mg daily for four to six weeks, then increase the dose to 10 mg daily. To taper donepezil, decrease the 10 mg daily dose to 5 mg daily for four to six weeks and then discontinue therapy. Pharmacists can recommend a GDR plan in consideration of pharmacokinetics (e.g., half-lives), pharmacodynamics, dose, and duration of medications.⁵¹

 

To achieve successful deprescribing, a trusting relationship, ongoing communication, and adequate documentation is essential between prescribers, pharmacists, pharmacy technicians, patients, and caregivers. Using the word “trial” is reassuring to patients and caregivers since it implies patients can restart the medication if needed.

 

Returning to Ms. Polly, the pharmacist can initiate the conversation with her daughter by saying, “I understand you feel overwhelmed. It seems now would be a good time to take another look at your mother’s medications. We can ease the burden of her medication regimen and simplify it for her. This trial of stopping a couple of her medications may help with her confusion and lower her fall risk.”

 

CONCLUSION

Deprescribing is an essential part of good prescribing and an important strategy. It ensure older adults are not taking suboptimal medications. Effective and safe deprescribing requires a patient-centered, shared decision-making approach with evaluation of preferences, level of functioning, life expectancy, and goals of care. Numerous clinical resources are available to reduce polypharmacy, assess benefit versus risk, and provide guidance and approaches for how to discontinue specific medications. Deprescribing inappropriate or unnecessary medications impacts clinical outcomes—such as reduction in hospitalizations, ED visits, falls and overall healthcare costs—mitigates ADEs, and improves quality of life. Simplifying more complex medication regimens may also improve patient adherence to essential medications.

 

With a strong foundation in deprescribing principles and tools, it’s time to reevaluate Ms. Polly’s medication regimen one last time. What other medications should be considered for deprescribing to reduce polypharmacy, mitigate ADEs, and improve quality of life for both Ms. Polly and her daughter?

 

Download CE Activity

INTRODUCTION

Ray and Kai are pharmacists that work together in a very busy outpatient clinic pharmacy. On a typical day, they fill around 800 prescriptions, and they usually have help from three technicians. Unfortunately, if anyone calls out sick or with an emergency, they don't have backup coverage.

 

Several times a week, patients return to the pharmacy and indicate that the prescriptions they received don't seem to be correct. Occasionally, Ray and Kai discover a medication error when patients indicate that their tablets or capsules don't look the same as a previous refill. Just yesterday, a mother returned to the pharmacy because her child’s liquid amoxicillin/clavulanate ran out before it should have. When Kai examined the label, she found a typographical error; it said, “take 5 mL three times a day” when it should have said, “take 2.5 mL three times a day.”

 

When staff members in this pharmacy identify medication errors, they usually discuss the problem quietly with the involved staff and make a mental note to implement corrective action or pay closer attention. Their pharmacy’s workload, staffing, error rate, and method of dealing with medication errors is not much different than many pharmacies across our nation. Throughout this continuing education activity, this example and others will help learners apply the lessons that experts have learned from analyzing medication errors.

 

Patient safety is a cornerstone of quality healthcare, and pharmacy professionals have an obligation to ensure patients receive safe and effective medications. Medication errors often stem from communication gaps, system complexities, or improper medication use. These errors not only compromise patient outcomes but also contribute to increased healthcare costs and increase risks of medication-related adverse effects.¹

 

The National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) tallies and analyzes medication error reports from the National Medication Errors Reporting Program, which is administered by the Institute for Safe Medication Practices (ISMP). NCC MERP defines a medication error as “any preventable event that may cause or lead to inappropriate medication use or patient harm.” Medication errors occur at various stages of the medication-use process, from prescribing and dispensing to administration and monitoring.² Recognizing these errors and implementing prevention strategies are essential to improving patient safety and advancing pharmacy practice.

 

OVERVIEW OF MEDICATION ERRORS

To truly appreciate medication errors’ impact on patients, pharmacy team members must recognize common terms and types of errors.

 

Medication Error Terminology

Several medication errors can arise in clinical and retail settings. To actively prevent patient injury through medication errors, it is important to know what to look for in practice. Terms to be familiar with in all pharmacy practice settings include^3,4:

• Adverse drug event (ADE): An injury resulting from medical intervention related to a drug
• Adverse drug reaction (ADR): An unintended reaction occurring at the intended drug dose
• High-alert medications: Drugs that bear a heightened risk of causing significant patient harm when used in error
• Look-alike/sound-alike (LASA) medications: Medications with similar-looking or similar-sounding names and/or shared features of products or packaging, leading to potential confusion
• Medication reconciliation: The process of creating the most accurate list possible of all medications a patient is taking—including drug name, dosage, frequency, and route—and comparing that list against the physician's admission, transfer, and/or discharge orders, with the goal of providing correct medications to the patient at all transition points

 

PAUSE AND PONDER: When an error is identified, how does your pharmacy respond?

 

Defining and Classifying Medication Errors

Table 1 lists common medication errors that may occur throughout the stages of medication use.⁴

Table 1. Common Medication Errors⁴

Error Type	Description	Examples
Prescribing	Errors occurring when ordering medication	Wrong drug selection, incorrect dose/frequency, illegible handwriting, incomplete prescription, drug interactions
Dispensing	Errors occurring during medication preparation and distribution	Wrong medication, wrong strength, wrong dosage form, incorrect labeling, look-alike/sound-alike drug confusion
Administration	Errors occurring during drug administration to the patient	Wrong route, wrong dose, wrong rate, omission, administering to the wrong patient
Monitoring	Errors occurring due to lack of proper patient monitoring	Failure to monitor for adverse effects, inadequate lab test follow-up, failure to adjust dose for renal/hepatic function

 

Most medication errors are preventable and can also be classified by the severity of their impact on the affected patient. Leading organizations, such as NCC MERP, have developed taxonomies to classify medication errors in more detail, including nine categories labeled A through I. These categories range from circumstances that have the capacity to cause error (Category A) to errors that result in patient death (Category I). While categories E through I describe varying degrees of harm to the patient, categories A through D involve situations with no patient harm. These classifications help institutions analyze trends and implement targeted interventions.⁵

 

Figure 1 displays NCC MERP’s medication error classifications with severity levels increasing from top to bottom.⁵

 

Figure 1. Medication Error Classification⁵

 

A patient comes in to pick up a prescription at Ray and Kai’s pharmacy and the line is out the door. As Kai retrieves the medication, she quickly confirms the patient’s last name and date of birth. Ray knows the patient and greets him; “Hey Charlie, how are the kids?” Kai then realized the prescription in hand was meant for a different patient by the name of Billy and was in the same bin. The correct medication is retrieved, and the patient safely receives what was actually prescribed, resulting in a near miss, rather than a full medication error.

 

Later, Ray and Kai sit down to reflect on what could have happened if the mistake hadn’t been caught in time. If the pharmacy dispensed the wrong medication and the patient noticed and brought it back before taking it, this would be an error, no harm situation. However, if the patient took the incorrect medication and experienced harmful adverse effects, it would result in an error, harm situation. In a more severe scenario, if the patient took the wrong medication and had an allergic reaction or other fatal outcome, it would be considered error, death. After discussion, Ray and Kai decide to speak to the staff about the importance of verifying patient information in full at every encounter. They relay a PRO TIP: employees can place prescriptions for patients with similar names in separate bins to avoid confusion.

 

Even the smallest and most routine tasks, such as verifying a patient’s identity, carry immense responsibility. Every action performed in a pharmacy setting has a direct impact on patient health. A moment of inattention or a skipped step can be the difference between preventing harm and causing irreversible consequences. That’s why it is crucial to approach every task, no matter how routine, with full attention and diligence

 

Beyond preventing individual mistakes, classifying and analyzing medication errors is a key to improving patient care on a larger scale. Recognizing and labeling these errors—whether they are near misses, errors with no harm, or more serious mistakes—provides valuable insight into when and where they happen. By identifying patterns, pharmacies can implement targeted safety measures to minimize risks.^4,5

 

ANALYSE, DOCUMENT, PREVENT

Medication Error Rates

To identify and reduce medication errors effectively, individuals and institutions must track their occurrences systemically. One of the most effective ways to achieve this is by calculating the medication error rate, which provides valuable insight into areas requiring improvement.⁶ The formula for calculating the medication error rate is as follows:

<<ADD IMAGE>>

 

The numerator represents the total number of medication errors recorded during a given period, with each error event counted as one. The denominator consists of all medication orders or doses that were dispensed and administered.⁶ This formula applies across all pharmacy settings, including both community and hospital environments.

 

 

For example, a hospital pharmacy dispenses 100,000 doses in a month and identifies 50 medication errors in that month. What is the medication error rate?

 

Once calculated, error rates are a crucial tool for identifying trends and implementing targeted interventions. By analyzing the data, healthcare teams can pinpoint high-risk areas, set measurable goals, and put corrective measures into action to minimize errors. This proactive approach not only enhances patient safety; it also optimizes pharmacy workflow and overall efficiency.

 

The pharmacy where Ray and Kai work is accredited. During an accreditation audit, one of the surveyors asks Ray about their medication error rate. Ray is unable to answer. The surveyor pushes a little and asks Ray to provide copies of all incident reports regarding medication errors. Ray finds two or three in which the medication error was serious enough to attract attention from the clinical staff or the clinic's risk manager. When the surveyor explains how to calculate a medication error rate, Ray listens carefully. Needless to say, the surveyor noted the lack of documentation about medication errors as a deficit in the survey and indicated that she did not believe that they only had three medication errors in the past year. When Ray and Kai meet to plan corrective action, they realize that without good documentation, they cannot make this calculation.

 

To ensure accuracy and reliability, all pharmacy and healthcare organizations must foster a culture of transparency and promote non-punitive error reporting.^6,7 Management must encourage staff to report errors without fear of retribution, allowing institutions to collect comprehensive data and develop effective mitigation strategies. Hospitals and community pharmacies can gain valuable insight into their performance by benchmarking their calculated error rates against institutions of similar size and complexity. Comparing rates with national standards or similar organizations helps ensure adherence to best practices and provides insight into additional potential interventions.⁷

 

Documenting Medication Errors

Pharmacists and technicians should know how to document and report incidents that occur in their pharmacy properly, usually following policies or procedures put in place by their institution and legal regulations. Unusual incident reports (UIRs) are a formal mechanism for documenting clinically significant medication errors and near misses.

 

Following identification of an incident and corrective patient measures, all relevant personnel should be notified and asked to record their recall of events. These reports should include key details such as who was involved, when and where the incident occurred, type of error, contributing factors, and corrective actions taken.⁸ To prevent recurrence of an incident or find a systemic issue leading to incidents, errors should regularly be recorded regardless of severity or whether it reached the patient or not. A PRO TIP is to maintain a list of errors that should be documented and keep unused UIRs in an accessible place (e.g., pinned on all desktops or stored in designated folders), encouraging staff to fill them out. These forms should be completed in full and a PRO TIP is to include instructions on what steps to take following the incident (i.e., read over and include any forgotten details, ensure all relevant staff is notified). Investigative staff should thoroughly gather data pertaining to the incident, including records, UIRs, patient notes, and physical items used in the event.⁹ Staff should establish a clear chronology of events to determine the root cause and prevent future occurrences.

 

Pharmacists and technicians should be well-versed in properly documenting and reporting incidents in their pharmacy, usually following institutional policies and legal regulations. UIRs serve as a formal mechanism for recording clinically significant errors and near misses. The following steps are necessary for proper documentation and reporting^8-10:

1. Identify and respond to the incident
   • When an error or near miss occurs, prioritize patient safety by taking corrective actions and notify all relevant personnel, including leadership.
2. Thoroughly document the incident
   • UIRs should capture key details such as
     1. who was involved
     2. when and where the incident occurred
     3. type of error and contributing factors
     4. corrective actions taken and follow-up measures
   • All involved personnel should document their recollection of events promptly to ensure accuracy.
3.  Encourage consistent reporting
   • To prevent recurrences and identify systemic issues, all errors—regardless of patient impact severity—should be recorded.
   • PROTIP: Maintain a list of errors that must be documented and keep unused UIRs easily accessible (i.e., pinned on desktops or stored in a designated folder) to encourage completion.
   • Forms should be fully completed, and staff should review their entries for accuracy before submission.
4.  Investigate and analyze the incident
   • Investigative staff should collect all relevant data, including UIRs, records, forms, and any physical items used in the event.
   • Establish a clear chronology of events to determine the root cause and prevent future occurrences.

 

UIRs are considered Quality Improvement data in healthcare organizations, making them confidential and generally protected from disclosure under laws like the Patient Safety and Quality Improvement Act.¹¹ Organizations use these reports internally to enhance patient safety and do not share them with patients or lawyers. However, protection can vary based on state laws and institutional policies, so a PRO TIP for organizations would be to highlight their specific policies and require additional training and separate filings to ensure proper procedures to maintain confidentiality.

 

Individuals must report serious medication errors resulting in patients harm or regulatory violations to state boards of pharmacy and should also report them to accreditation agencies (e.g., Joint Commission) and the FDA through the MedWatch program.⁸ Pharmacy personnel is expected to know how and when to use institution-specific forms and to revise these to simplify and encourage the error reporting process.

 

Ray and Kai are motivated to track medication errors better. When they dust off their stack of unused UIR forms, they realize that their forms are skeletal and their organization would benefit from a better tool. One of their technicians, Tara, volunteers to look at a number of different forms and identifies four. The staff chooses to “pilot” two, meaning they will document all medication errors that occur over the next three weeks on both forms, and then analyze the results. At the end of the pilot, they choose one form but realize that they need to tailor it to their practice. Tara also notes that they could automate the form and include a picture of the dosage forms that were involved.

 

Within three months, Ray and Kai realize from the pictures that a full 25% of their errors involve tablets that are white. Ray and Kai can share a PRO TIP with other organizations now. They create a whiteboard that lists most of their white tablets and the tablet markings. The technicians who handle inventory update the whiteboard when they change generics. Additionally, whenever Ray or Kai visually verify a prescription for a white tablet, they note the tablet marking on the prescription. In this way, they eliminate a good number of errors.

 

Institutions may have different methods for documenting unusual incidents, so it is essential that pharmacy staff know how to access and properly complete these forms. Keeping UIR forms up to date ensures they remain effective and relevant. Attached are three different incident report forms; review them carefully and identify their similarities and differences (see Appendix).^12-14

 

Accurate medication error reporting is the underpinning of identifying risks and improving patient safety. However, traditional error-reporting systems often capture only a portion of actual incidents and do not usually account for adverse effects. This could be attributed to limitations in error-reporting, including but not limited to underreporting due to fear of punishment, time-consuming processes, and a lack of feedback and follow-up.¹⁵ Research suggests that the use of observation, when appropriate and feasible, could lead to more accurate detection of medication errors in practice.^16,17 When applicable, institutions can use observation in combination with tracking error reports and greatly reduce the frequency of medication errors.

 

A strong culture of safety in pharmacy practice encourages transparent error reporting and non-punitive responses. Employees should feel comfortable reporting mistakes without fear of disciplinary action, as this fosters a learning environment rather than a blame culture. Encouraging reporting allows institutions to^7,18

• identify error trends and implement preventative measures
• provide additional training where needed
• improve medication safety policies and procedures

 

All people in positions of authority should encourage pharmacy personnel to report medication errors to their institutions and to the FDA, ISMP, or NCC MERP if appropriate.¹⁹

 

System-Based Prevention Approaches

Healthcare institutions implement structured systems to enhance workflow efficiency and minimize medication errors. These systems provide standardized protocols, technological advancements, and communications strategies that help pharmacy personnel ensure safe and accurate medication dispensing and administration.

 

With advancements in technology, healthcare professionals frequently rely on automated systems to assist with medication safety. While these tools greatly reduce the potential for human error, they should be used to complement, not replace, pharmacist and technician expertise. Proper training and implementation of these tools are essential to their effectiveness. Key technologies that reduce medication errors include the following^18,20,21:

• Barcode scanning as an additional verification step in the dispensing and administration process ensures that the correct drug, dose, and patient matches the prescription and manufacturer specifications.
• Computerized provider order entry (CPOE) and e-prescribing reduce errors by eliminating the risk of misinterpreting handwritten prescriptions. CPOE also alerts prescribers about potential drug interactions, allergies, and dosing errors before orders are processed.
• Automated dispensing cabinets, commonly used in hospitals, help regulate medication storage, access, and tracking to prevent unauthorized or incorrect dispensing.

 

To maximize these systems’ effectiveness, pharmacy staff must remain vigilant, ensuring that they do not blindly trust automation. As recommended by the ISMP, conducting manual double-checks judiciously, selective to certain high-risk tasks or medications, can further enhance patient safety.²²

 

Familiarizing all staff with institutional standard operating procedures (SOPs) is essential for ensuring consistent and safe practice. These guidelines outline step-by-step procedures for specific pharmacy operations, reducing deviations that could lead to medication errors.²³ When adhered to properly, SOPs standardize processes (minimizing variability and human error), provide clear instructions for handling high-alert medications, and outline best practices for prescription verification, dispensing, and patient counseling.^21,23 For example, a hospital SOP may require two licensed healthcare professionals to verify chemotherapy doses independently before administration. In a community pharmacy, an SOP may require mandatory counseling for first-time prescriptions of high-risk medications, such as opioids or anticoagulants. Having SOPs and checklists readily accessible ensures that pharmacy personnel can reference best practices quickly when dealing with complex or high-risk situations.

 

SIDEBAR: A Word About CHECKLISTS

When checklists are numerous in quantity and poor in design, pharmacy staff may experience a sense of checklist fatigue, becoming overwhelmed and disengaged with completing them. This could lead to rushed or skipped steps, negatively impacting performance and patient safety. The following lists some strategies to avoid feeling desensitized to the repetitive nature of checklists^22,24,25:

• Use checklists selectively by focusing on the most important or highest-risk tasks
• Improve the design to be clear, concise, and easy to follow
• Avoid unnecessary or redundant steps
• Regularly ensure the checklists are up-to-date and effective
• Address fatigue with staff and provide training and feedback on the importance of each step

 

PAUSE AND PONDER: When reviewing a prescription, what red flags should prompt you to double check with a prescriber, pharmacist, or colleague?

 

PHARMACY PRACTICE CONSIDERATIONS

Each pharmacy practice type has its own unique concerns and considerations with regard to medication error reporting.

 

Community Pharmacy

In a retail or clinic pharmacy setting, like the one in which Ray and Kai work, pharmacists and pharmacy technicians must exercise caution throughout the prescription filling process to prevent errors. These errors can be minor and initially go unnoticed, but can lead to serious adverse events, hospitalizations, or even fatalities if not promptly identified and addressed.²⁶

 

The first stage of medication processing—receiving a prescription—creates a significant risk for errors. Whether prescriptions are transmitted electronically, by phone, or handwritten, pharmacy personnel may misread, misinterpret, or fail to recognize important details.²⁷ Especially in high-volume settings, healthcare professionals should prioritize accuracy by seeking prescriber clarification when needed, rather than making assumptions or rushing through interpretation.  Errors can also originate from prescribers, and pharmacy personnel should have a high index of suspicion that every prescription is incorrect. Calling to clarify questionable doses or frequencies ensures patient safety and may also prompt prescribers to recognize and correct unintended mistakes.²⁶ All three errors that Ray and Kai documented had been serious enough to result in an ADE or ADR. When they looked back at these errors, they realized that for two of them, if they had questioned the patients or called the prescribers, the errors may have been avoided entirely.

 

Common errors that pharmacists and technicians should be vigilant about in community pharmacy include^1,3,27,28

• Misinterpreting abbreviations and symbols: Sloppy abbreviations and symbols can lead to dangerous dosing errors. Table 2 summarizes the Joint Commission’s “DO NOT USE” list of abbreviations that should be displayed in pharmacies.
• LASA medications: Medications with similar names can be easily confused if not carefully verified.
• Incorrect dosing and strength selection: Errors can occur by selecting the wrong strength of a medication or miscalculating pediatric or weight-based doses.

 

Table 2. The Joint Commission’s “DO NOT USE” List²⁸

Do Not Use	Potential Problem	Use Instead
U, u	Mistaken for “0” (zero), the number “4” (four) or “cc”	Write “unit
IU	Mistaken for IV (intravenous) or the number 10 (ten)	Write “International Unit”
Q.D., QD, q.d., qd   Q.O.D., QOD, q.o.d., qod	Mistaken for each other   Period after the Q mistaken for “I” and the “O” mistaken for “I”	Write “daily”   Write “every other day”
Trailing zero (X.0 mg) * Lack of leading zero (.X mg)	Decimal point is missed	Write X mg Write 0.X mg
MS   MSO4 and MgSO4	Can mean morphine sulfate or magnesium sulfate   Confused for one another	Write “morphine sulfate”   Write “magnesium sulfate”

*Exception: A trailing zero is only allowed when necessary to indicate the exact level of precision, such as in laboratory results, imaging studies that report lesion sizes, or catheter/tube sizes. It may not be used in medication orders or other medication-related documentation.

 

Maintaining readily accessible reference lists can help pharmacy personnel cross-check potential medication errors before contacting prescribers. The ISMP has identified numerous LASA pairs that contribute to medication errors and has created lists of commonly confused abbreviations and symbols.²⁹ Additionally, using TALL Man lettering (e.g., capitalizing part of a drug's name in upper case letters to differentiate similar drug names like hydrALAzine vs hydrOXYzine) when documenting or labeling LASA medications can minimize confusion.²⁹

 

In the hypothetical pharmacy, Ray notes that one of the technicians consistently fills prescriptions for dipyridamole with diphenhydramine. He has pointed this problem out to the technician several times and asked the technician to find the correct medication, but the problem continues. After learning about TALL Man lettering, he realizes that their computer system does not use this simple but useful intervention. He contacts the programmers and asks if they can make the changes, providing the ISMP's list of drugs for which this intervention could prevent many errors. A PRO TIP here is to ask the technician to use a highlighter to highlight the part of the drug name that follows "DIP-" on all drugs that begin with these three letters before filling prescriptions.

 

Errors often arise during the later stages of prescription processing, including data entry, assembly, and pharmacist verification. Pharmacy personnel may rely too heavily on the auto-populated fields in electronic prescribing systems (e.g., McKesson, PioneerRx), assuming the information is correct without double-checking key details. This could lead to incorrect medication strengths, frequency, or refill quantities, ultimately causing billing issues or improper medication dispensing.^27,20

 

Dispensing the wrong formulation can occur if pharmacy staff select similar-looking bottles. Barcode scanning technology can help reduce assembly errors by ensuring use of the correct product. Pharmacists must physically inspect medications rather than relying solely on electronic systems. Pharmacy staff should attach medication guides, auxiliary labels, and other patient education materials as necessary. Pharmacy professionals must recognize that technology is a tool, not a replacement for human oversight. Systems may have glitches or auto-fill errors, and staff should remain vigilant to manually verify accuracy when needed. ²⁰

 

Over the few weeks after the accreditation survey, Ray and Kai see a number of minor medication errors in the pharmacy. During a counseling session, Kai learns that one patient has been taking a diuretic but has not been increasing the amount of potassium in her diet. The patient reports cramping and nausea. Kai realizes that the pharmacy staff stopped using colorful auxiliary labels, assuming that the key counseling points are covered in the multi-page handout that the computer prints with each prescription. Unfortunately, many patients simply throw that multi-page handout into the recycle bin (as did this patient). Kai realizes that using auxiliary labels is an opportunity to improve counseling and to increase the likelihood that patients will take medications correctly.

 

The final step in the prescription process—dispensing the medication to the patient—requires uninterrupted attention to detail. Staff often overlook or rush this step in busy retail pharmacies, especially under pressure from patients who may be in a hurry. Patients who are eager to leave or have pressing time constraints may create an environment where staff feel rushed to complete the transaction quickly, potentially compromising safety. The Joint Commission requires two patient identifiers before dispensing a medication (e.g., full name and date of birth) to prevent mix-ups.²⁶ Failing to confirm the patient’s identity may result in a patient receiving the wrong prescription, leading to serious consequences.

 

While not all patients will ask for counseling, it is the pharmacy staff’s responsibility to offer counseling proactively, especially in critical situations. Pharmacy staff must remain alert to identify potential medication errors and recognize when pharmacist intervention is necessary. Pharmacy technicians are essential to this process. In our hypothetical pharmacy, Ray and Kai realize that the way that they've been dealing with medication errors isn't conducive to ideal teamwork. Further, they realize that they need to engage their technician support team so the pharmacist becomes involved in the process earlier when technicians see red flags.

 

Common errors that require technician awareness and referral to the pharmacist include^2,4,20

• misuse or incorrect administration
• first-time prescriptions, dose changes, or class switches
• high-risk medications or drug interactions
• duplicate therapy or overlapping prescriptions

 

By actively engaging in patient education and ensuring clear communication at the point of dispensing, pharmacy professionals can significantly reduce medication errors and enhance patient safety. A PRO TIP comes from the Indian Health Service where pharmacy staff take a few minutes to remove medication from the bag, read the drug name, open the bottle, shake a few dosage units into the cap, and show it to the patient. Patients may identify medications that look different than they remember, which may signal a change in generic supplier or may identify an error. Although this process sounds time consuming, it actually takes just a few seconds for each bottle, and it prevents adverse outcomes in many cases.

 

Hospital Pharmacy

Hospital pharmacists and pharmacy technicians have serious responsibilities in ensuring safe medication use among high-risk patient populations. Like patients seen in the community, hospitalized patients often have complex conditions, multiple comorbidities, and require high-alert medications. But any event that precipitates hospitalization increases vulnerability to medication-related adverse events.²¹ Learners should note that many of these interventions apply in community centers as well.

 

Similar to retail or clinic pharmacy, miscommunication between prescribers and pharmacy personnel remains a leading cause of medication errors in hospitals. Healthcare providers can reduce errors through effective communication, verification, and collaboration. Regularly confirming prescription details and clarifying discrepancies helps prevent errors before they reach patients. Pharmacy staff need to establish trust and employ open communication with prescribers to ensure patient safety in hospitals. A breakdown in interprofessional relationships can lead to medication errors, such as^18,21

• incorrect medication selection due to misinterpreted verbal or written orders
• dosing errors, particularly in pediatric or renally impaired patients, when key patient information is not communicated
• failure to adjust medications in response to changing renal or hepatic function, leading to toxicity or subtherapeutic dosing
• missed allergy documentation, resulting in patients receiving medications that trigger adverse reactions

By fostering a culture of open dialogue and verification, hospital pharmacy teams can minimize preventable errors and ensure optimal patient care.

 

Consider a hospital pharmacy that employs nine pharmacists on three shifts, with a staffing ratio of one pharmacist to two technicians throughout the entire 24 hours. This pharmacy does a better job of documenting medication errors on unusual incident reports, but considerable room for improvement remains. Lisa is the pharmacist who works closely with the Performance and Quality Improvement (QPI) Department. Her liaison in QPI notifies Lisa that of the 46 medication errors reported in the last quarter, eight were associated with orders from a hospitalist, Dr. Backoff, who rotates shifts. The underlying cause seems to be miscommunication. Dr. Backoff is well known for his offensive behaviors; he humiliates people who ask questions, intimidates coworkers using insults or repeatedly bringing up past errors, excludes staff from opportunities to participate, and is generally so critical that people avoid him.³⁰

 

When staff call Dr. Backoff, he often fails to return the call. Over time, the situation has escalated to the point where staff are afraid to pick up the phone and call him when problems occur. As Lisa works with her QPI liaison, they realize that their workplace has no comprehensive policies and procedures targeting workplace bullying. Without clear guidelines and protocols, people who are targeted by bullies may feel powerless and unwilling to work with their bully.³¹ A PRO TIP is that this organization needs to develop training to address bullying, and Lisa and the QPI liaison need to speak to Dr. Backoff's supervisor immediately. The supervisor can refer Dr. Backoff to employee assistance program or implement corrective and disciplinary action.

 

Certain medications require heightened safety precautions due to their potential for severe patient harm if misused. The ISMP has a list of high-alert medications that require extra safeguards in hospital settings. An example of these are anticoagulants; even small dosing mistakes could lead to severe bleeding or thrombosis (clotting).³² Due to the serious risks associated with high-alert medications, pharmacy staff pharmacists and pharmacy technicians should double-check and arrange independent verification consistently.²¹

 

Medication errors frequently occur during transitions of care, including hospital admission, transfers to other facilities (e.g., long-term care, rehabilitation), and discharge to home. These errors can result in unintentional medication discontinuation, dose and frequency errors, or discharge medication miscommunication, significantly increasing patients’ risk of harm.³³  One of the most significant risks during transitions of care is unintentional medication discontinuation (mistakenly stopping an essential chronic medication). Dose and frequency discrepancies and miscommunications about discharge medications further increase the risk of ADEs post-hospitalization.³⁴

 

To prevent these errors proactively, hospital pharmacists and pharmacy technicians should^21,33

• conduct a thorough medication reconciliation at the time of admission, ensuring all home medications are accurately documented
• maintain clear, updated medication lists through each stage of hospitalization
• collaborate to ensure patients and caregivers receive comprehensive discharge counseling, with the technician reminding or prompting pharmacists if this step is missed, and reinforcing medication changes adherence instructions

 

Lisa’s hospital has a structured transitions of care program. They hire pharmacy students to conduct medication reconciliation under a pharmacist’s supervision. Before pharmacy students can conduct medication reconciliation, they complete a comprehensive training program. Regardless, errors on the medication list still slip through.

 

Lisa's hospital is not alone with this problem. Many hospitals find that errors occur even after medication reconciliation. A 2024 study of the medication reconciliation process and related medication errors indicates that these processes are “very heterogeneous,” meaning that in some areas, medication reconciliation was very good and in others, not so much.³⁵ They found that error rates were unexpectedly high in some areas. This study looked at 929 prescriptions written for 182 patients. In 91% of cases, the reconciler had not specified the drug form. About 72% of medication administration errors pursuant to a faulty medication reconciliation exercise resulted in patients receiving the wrong release dose formulation (i.e., immediate release as opposed to extended release). The researchers indicated that medication error rates did not improve significantly over the period before they conducted routine medication reconciliation.³⁵

 

Lisa has heard coworkers talk about medication reconciliation as a useless process and seeing them roll their eyes when they look at a medication reconciliation report that has obvious errors. In the past, pharmacy staff did not consider a mistake on a medication reconciliation list to be a medication error. However, when a serious error slips through, Lisa’s QPI liaison suggests that they began tracking such errors on unusual incident reports. A PRO TIP here is to track errors in medication reconciliation and try to identify the areas where errors are most likely to occur in the medication reconciliation process. At this hospital, Lisa and the QPI liaison were able to confirm that they also had a problem with identification of the correct formulation. Over the following months, they were able to improve by using additional training and revising their medication reconciliation form to force technicians to ask about the formulation or to see the bottle.

 

PAUSE AND PONDER: Can you think of any processes or policies in your workplace that can be improved to enhance patient safety?

 

Pharmacist and Technician Responsibilities

Pharmacy professionals have a responsibility to actively communicate with their colleagues and other healthcare providers to prevent errors. Effective collaboration within the healthcare team ensures safe medication practices by¹⁸

• clarifying unclear or incomplete prescriptions before dispensing
• confirming appropriate dosing adjustments for renal or hepatic impairment
• coordinating medication reconciliation during transitions of care to prevent omissions or duplications

 

Management needs to empower pharmacists and pharmacy technicians to voice concerns regarding potential medication errors. Addressing these concerns professionally and respectfully fosters a culture of teamwork and patient safety.

 

A key responsibility of pharmacy professionals is to provide clear, understandable medication counseling to patients. However, it is unrealistic to expect that staff can counsel all patients on every detail of their prescription. Instead, pharmacists should prioritize the most critical points, especially on new prescriptions, including³⁶

• dosing instructions and adherence importance
• common and serious adverse effects
• drug interactions and contraindications
• proper storage and administration techniques

 

One effective counseling strategy is the teach-back method, where patients repeat the pharmacist’s instructions back in their own words. This ensures patients fully understand how to use their medication correctly. For example, when dispensing doxycycline, instead of simply stating “Take this with a full glass of water,” a pharmacist using the teach-back method would ask one simple question after explaining how to take the doxycycline: “Can you explain to me how you will take this medication to avoid stomach irritation? I need to be sure I covered everything.”^18,21,26 

 

When a serious medication error occurs, it is crucial to investigate the underlying causes to prevent future occurrences. Root-cause analysis (RCA) is a structured problem-solving method used to analyze errors after they have happened—including what, how, and why it happened—and can help determine what lessons could be learned and how to reduce the risk of recurrence and make care safer.^3,21 For example, if a retail pharmacy dispenses the wrong insulin type and a patient is subsequently hospitalized, an RCA might reveal that the error stemmed from look-alike packaging and a lack of independent verification.

 

Failure mode and effects analysis (FMEA) is a proactive approach to medication safety, identifying potential failures before they occur. By evaluating processes and pinpointing high-risk areas, institutions can implement safeguards to prevent errors before they reach patients.²¹ For instance, before introducing a new automated dispensing cabinet, an FMEA could help identify potential failure points, such as medication selection due to user interface design, allowing for preventive modifications.

 

CONCLUSION

Patient safety is a fundamental pillar in pharmacy practice, and reducing medication errors requires a proactive, systematic approach. Errors can occur at any stage of the medication use process, from receiving and interpreting prescriptions to dispensing and patient counseling. Recognizing common errors—such as abbreviations, LASA drugs, incorrect dosing, and transcription mistakes—helps pharmacy professionals to implement safeguards that prevent harm.

 

 

 

 

 

 

 

 

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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 Reactions13-15
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.^26,27 Probiotics 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.⁵⁰ This 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.⁶⁰ Trimethoprim 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.⁶⁴ Daptomycin’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.

 

 

 

 

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INTRODUCTION

 

Did you know that the ketogenic diet was NOT initially created for weight loss? Recently, the “keto” diet has become another fad diet for people trying to lose weight. Since 2000, more researchers have started to study the ketogenic diet, causing an increase in dieters who are employing this diet.¹

 

For decades, various entities have promoted fad diets as a way to lose weight and accrue other health benefits, with no data to back them up. The ketogenic diet began to reach the public’s consciousness in the 1970s, gained popularity in the early 2010s, and by 2017, it was a frequent topic in national news media. Google searches for the ketogenic diet (sometimes called the paleo diet, which is similar but not identical) quadrupled that year; questions about this diet were in the top 10 health questions.² Many people started using the ketogenic diet without understanding how it works or its associated benefits and risks. In 2014, celebrities like Lebron James, Kim Kardashian, and Megan Fox started using the ketogenic diet during its fad weight loss phase. In 2020, around 6% of Americans were consuming a ketogenic, high fat diet.³

 

In the 1920s, researchers noticed that some patients with epilepsy experienced benefits during fasting, so they discovered a way to mimic fasting to treat the disease.¹ Soon, physicians began to use the ketogenic diet for its antiepileptic properties.¹ However, in the next decades, researchers introduced antiepileptic medications and the ketogenic diet’s popularity faded. Treatment for epilepsy still includes some of the first antiepileptic medications: phenobarbital and phenytoin.⁴ Although physicians began using phenobarbital in 1912 for epilepsy, the U.S. Food and Drug Administration did not approve phenytoin for use in epilepsy until 1938.⁵ In the 1940s, clinicians used troxidone, but its toxicity profile was unacceptable. Ethosuximide, approved in 1958, replaced it. Approval of carbamazepine and valproic acid in the 1960s made the ketogenic diet unnecessary and obsolete for the most part.⁵

 

Although pharmacists are the medication experts on the clinical team, they must understand all types of treatment, including nonpharmacologic interventions. During a ketogenic diet, patients eat a limited number of carbohydrates so the body will enter ketosis. Because of the diet’s intensity, pharmacists and technicians need to understand how the diet works to ensure patient safety. When patients start or are on the ketogenic diet, pharmacists need to counsel patients to ensure no drug interactions occur. Pharmacists also need to counsel patients who may have started the diet by themselves about its benefits and the risks. Also, remember interested dieters might embrace a New Year's resolution regarding ketogenic dieting, because National Keto Day is January 5th!

 

This continuing education activity summarizes knowledge of the ketogenic diet, the diet’s mechanism and its positive and negative effects, current medical uses for patients with epilepsy, diabetes, polycystic ovary syndrome (PCOS), and others, and recommendations for patient education and counseling.

 

KETOGENIC DIET

 

The ketogenic diet alters how the body burns energy, from carbohydrates to lipids. The traditional food pyramid places fats in the smallest section at the top, with carbohydrates in the largest bottom section. The ketogenic diet flips the pyramid, so most recommended foods are fats and very few are carbohydrates.

 

According to the Dietary Guidelines for Americans, 25% to 35% of an adult’s diet should come from fats, 45% to 65% from carbohydrates, and 10% to 30% from protein.⁶ In a 2000 calorie day for ketogenic diet patients, fat should account for 70% to 80% or 165 g of daily caloric intake.⁷

 

Although an exact timeframe is unknown, researchers believe that it can take the body up to four weeks to adapt to the ketogenic diet and ketosis.⁸ Patients initiating the diet could try daily exercise to force the body to break down fats, but its efficacy for reducing time to ketosis is unknown.⁸

 

Ketogenesis

 

The ketogenic diet uses ketosis and ketogenesis. When people eat carbohydrates, the body uses cellular respiration to produce energy from breaking down glucose molecules. However, if no carbohydrates are available, which would be the case during extended exercise or fasting periods, the body will naturally enter ketosis. Ketosis is a state of elevated ketone bodies, which include beta-hydroxybutyric acid, acetoacetic acid, and acetone in the blood.⁹ When the body needs energy, ketogenesis occurs to produce these ketone bodies, which can be used as an alternative energy source.

 

In normal cellular respiration, acetyl-CoA is condensed with oxaloacetate to begin the citric acid cycle. Beta-oxidation of fatty acids can produce acetyl-CoA, similar to the production of acetyl-CoA from glycolysis of glucose. In times of reduced glucose (i.e., fasting, extended exercise, ketogenic diet), the body diverts the acetyl-CoA produced from the fatty acids into ketogenesis.

 

Ketosis begins with fatty acid oxidation and the production of acetyl-CoA. Using the enzyme 3-ketothiolase, acetyl-CoA is converted into acetoacetyl-CoA. Then, the enzyme HMG-CoA synthase converts acetoacetyl-CoA to HMG-CoA.⁹ Low glucose levels during starvation or a high fat diet—a signal that the body needs to produce an alternative energy source for the brain—trigger this step of ketogenesis.¹⁰

 

The last step of energy production during ketosis is the conversion of HMG-CoA to the ketone bodies acetoacetate (AcAc) and 3-beta-hydroxybutyrate (3HB). Using HMG-CoA lyase, AcAc and 3HB are cleaved from HMG-CoA.⁹ By being in a constant state of ketogenesis from eating fatty foods, patients on the ketogenic diet change their natural fuel source from glucose to ketone bodies.

 

Ketone Bodies

 

The 3 main types of ketone bodies are AcAc, 3HB, and least commonly, acetone. The liver produces AcAc, 3HB, and acetone in a 78:20:2 ratio, respectively, during fatty acid oxidation.¹¹ Acetone is produced the least because it’s the byproduct of the uncommon and spontaneous decarboxylation of 3HB.¹¹ Ketone bodies are the only non-glucose derived energy source for the brain.¹⁰ The brain cannot process fatty acids, so they must be converted into ketone bodies first. They provide energy to the brain because both AcAc and 3HB can diffuse across blood brain barrier.⁹

 

During a normal day, ketone bodies account for only 2% to 6% of an individual's energy requirements. However, after a three- to four-day fast, ketone bodies account for 30% to 40% of the body's energy source.⁹ The liver can produce 185 grams of ketone bodies daily, which is enough to satisfy a person’s daily energy needs.⁹

 

By using ketone bodies, patients can avoid breaking down carbohydrates as an energy source, similar to how the body naturally functions during fasting. Ketone bodies are thought to have a direct beneficial mechanism, which will be discussed later, in disorders like epilepsy.

 

Effects of Insulin and Glucagon

 

Insulin and glucagon are important in ketosis and ketone bodies. Low insulin levels trigger steps in the ketosis process. Insulin, also called the antiketogenic hormone, decreases 3HB production, whereas glucagon, the ketogenic hormone, increases 3HB production.¹²

 

When humans consume carbohydrates and blood glucose levels rise, the pancreas releases insulin to absorb the blood sugar for energy storage.¹³ Insulin inhibits hormone-sensitive lipase and HMG-CoA synthase, enzymes that take part in fatty acid breakdown. It also stimulates acetyl-CoA carboxylase, causing the conversion of acetyl-CoA to malonyl-CoA, and blocking fatty acid transport into the mitochondria.¹⁰ As a result, insulin decreases the need for fatty acid oxidation and ketone bodies are decreased. The ketogenic diet requires patients to avoid carbohydrates to diminish insulin production and promote these mechanisms.

 

Glucagon does the opposite of insulin. The body uses epinephrine and glucagon to stimulate adipose (fat) tissue to produce more fatty acid.⁹ Glucagon triggers phosphorylation of hormone-sensitive lipase and HMG-CoA synthase, thus promoting ketogenesis.⁹ The body releases fatty acids from triglycerides, so they can be broken down by the newly activated enzymes.

 

A successful ketogenic diet requires a high glucagon/insulin ratio, similar to that experienced during fasting and by patients with diabetes. The high ratio increases fatty acid production and oxidation. Ketogenesis will follow.

 

Foods Consumed

 

Most foods for a ketogenic diet will have moderate amounts of proteins, no carbohydrates, with many fats. To prevent heart disease, physicians and pharmacists can counsel patients to eat healthy fats. Table 1 describes some examples of foods that are common in the ketogenic diet.

 

Table 1. Food Options Commonly Used in the Ketogenic Diet¹⁴

Fish and Seafood	-        Full of protein -        No carbs -        Associated with positive cardiovascular and health benefits
Poultry and Meat (Chicken, beef)	-        Rich in protein -        No carbs -        Limit processed meats
Nuts (Almonds, walnuts, pecans, cashews)	-        High in fiber, protein, and unsaturated fats -        Very low carbs -        Antioxidants
Non-starchy Vegetables (Broccoli, green beans, bell peppers)	-        Include other vitamins and nutrients -        Antioxidants
Cheese	-        No carbohydrates -        High in fats, protein, calcium -        Too many saturated fats
Avocados	-        Potassium, unsaturated fats -        Most carbohydrates in avocados are fiber

 

Patients on the ketogenic diet must understand how to track their nutrition to diet properly, calculating proteins, carbohydrates, and fats daily. Patients must calculate carbohydrates to account for dietary fiber because fiber is not digested with other carbohydrates.¹⁴ When tracking nutrition, patients on the ketogenic diet must track net carbohydrates, which can be found by subtracting the dietary fiber content from the total carbohydrates. The total carbohydrate level reported on nutrition labels does not accurately reflect the carbohydrate content the patient has consumed.

 

Most of the foods mentioned in Table 1 are high in fat. Fish, seafood, meat, poultry, and eggs are main staples. Processed meats, like bacon, should be eaten more sparingly compared to non-processed meats, like chicken and beef.¹⁴ Patients can eat chicken and fish more frequently because they promote cardiovascular health, unlike red meat. Many people believe that berries are not allowed on the ketogenic diet, but strawberries, raspberries, and blackberries have very low net carbohydrates. The total carbohydrates in berries may appear high, but their high fiber content allows berries to have a low net carbohydrate content.

 

A vegetarian ketogenic diet is a possibility, even though options are more limited. Vegetarian options with high protein and low carbohydrates include nuts, tofu, and seitan (a meat substitute made from the gluten in wheat).¹⁵ These dieters can also enjoy peanut butter-based desserts for more proteins. Seeds are high in fat and have high dietary fiber. For higher calorie meals, eggs and dairy (hard cheeses and plain yogurt) are an important fat option. Eggs have many fats, but essentially no carbohydrates.¹⁵

 

Any food that is high in net carbohydrates will disrupt the body's ketosis. These are foods like starchy vegetables, juices, syrup, chips, and crackers.¹⁴ Foods high in carbohydrates will give the body enough energy to not oxidize fatty acids and prevent the production of ketone bodies.¹⁴

 

PAUSE AND PONDER: Would a fasting patient reach ketosis quicker than a patient who is not fasting?

WHO BENEFITS FROM THE KETOGENIC DIET?

Obesity

Obesity, a leading risk factor for many chronic health conditions, continues to rise in the United States. According to the CDC, the prevalence of diabetes has increased to 41.9% from 2017 to 2020.¹⁶ Many have adopted low-carbohydrate, high fat lifestyles to lose weight. A 2016 meta-analysis of 11 randomized control trials assessed the efficacy of the ketogenic diet. Among the 1369 participants, those on the ketogenic diet experienced greater weight loss than those who participated in a low-fat diet.¹⁷ After six months to two years of intervention, patients experienced significant weight loss, HDL cholesterol increase, and triacylglycerol (TAG) reduction. The studies were limited by moderate to high heterogeneity and possible publication bias. A 2021 study evaluated the efficacy of the ketogenic diet using a mobile health application in comparison to a calorie restricted, low-fat application.¹⁸ Of the 155 participants, those using the ketogenic diet app experienced greater weight loss (12.3 pounds) at 12 weeks. Hemoglobin A1c (HbA1c) and liver enzymes also improved for the ketogenic diet group. This study was limited by operating fully remotely via the application. Patients could have benefited from in-person counseling or on-site visits to promote adherence.¹⁸

Another meta-analysis of 13 randomized controlled trials showed that participants on the ketogenic diet benefited from greater weight loss than those on a low-fat diet proving that the ketogenic diet can be used for obese patients. The low-fat diet group consisted of 787 patients while the ketogenic diet group consisted of 790. Patients that were part of the keto group lost approximately 3.6 pounds (1.6 kilograms) more than the low-fat group.¹⁹ Patients saw a greater increase in HDL and a more significant reduction in TAG in the keto group.

Type 2 Diabetes

Patients with type 2 diabetes (T2D) sometimes benefit from the ketogenic diet through improved glycemia and reduced insulin resistance. A study of 28 patients with T2D following a ketogenic diet showed that blood glucose and HbA1c improved. The ketogenic diet could potentially help patients with T2D reduce the number or dose of medications.²⁰ Another comparative study showed that obese patients with T2D had improvement in blood glucose profiles, insulin sensitivity, and HbA1c when adhering to the ketogenic diet for two consecutive weeks.²¹ However, the study was limited by short duration and small sample size.

Polycystic Ovary Syndrome

Similar benefits seem to apply to patients with polycystic ovarian syndrome (PCOS). Patients with PCOS experience hyperandrogenism, insulin resistance, and ovulatory dysfunction.²² Current treatment options include metformin, clomiphene, and letrozole; the ketogenic diet may provide good results for these women through insulin reduction.

In addition to the symptoms listed above, women with PCOS tend to gain weight, develop acne, and experience hirsutism.²³ Physicians recommend lifestyle modifications and hormonal contraceptives as first line interventions, but often, these interventions are insufficient, and symptoms persist.²³

Researchers have conducted many studies to evaluate the benefits of the ketogenic diet for women with PCOS, yet the studies are greatly limited by sample size. For example, a 2019 study consisting of 14 women with PCOS struggling with their weight assessed changes in body weight, BMI, fat body mass, lean body mass, HDL, and several other parameters. At 12 weeks, participants saw a 9.43-kilogram (20.7 pound) reduction in body weight, 3.35 reduction in BMI, and an 8.29-kilogram (18.2 pound) reduction in fat body mass.²³

A pilot study consisting of five women tested the ability of the ketogenic diet to reduce PCOS symptoms. Researchers provided the women with low-carbohydrate diet books and handouts alongside group meetings to test the ketogenic diet’s efficacy for PCOS. Participants consumed fewer than 20 grams of carbohydrates per day for six months. To test participants’ adherence, researchers measured ketones and body weight. Throughout the 24-week period, participants lost weight with a mean BMI decrease of four kilograms (approximately 8.8 pounds) which was a 14.3% total reduction in body weight.²⁴ The study resulted with clear reductions in testosterone, fasting serum insulin, and an overall improvement of PCOS symptoms.

Additionally, an eight-week crossover study involving 30 women with PCOS demonstrated various benefits. On average, weight loss ranged from 1.3 to 1.6 kg (2.8-3.5 pounds). When compared to baseline, the results of this study highlight the relationship between decreases in testosterone and fasting insulin.²⁵ Overall, improvements in insulin resistance, testosterone levels, and weight loss, the ketogenic diet may help patients with PCOS.

Epilepsy

The original use for the ketogenic diet was as an antiepileptic therapy in children.¹ After the discovery of antiepileptic medications, the need for the ketogenic diet diminished. However, researchers are bringing the ketogenic diet back to help treat patients who are refractory to modern antiepileptic medications.

In combination with medications, researchers have seen up to a 50% reduction in the number of seizures patients are having, with 10% to 15% becoming seizure free.²⁶ Co-administration with antiepileptics is possible for some medications. However, most patients are children and maintaining this strict diet is difficult.

During a retrospective study, researchers compared the effects of the ketogenic diet to modern anticonvulsant medications in 150 children. At one year, 55% of patients remained on the diet, and 27% of the patients who remained in the trial had a greater than 90% decrease in seizure frequency.²⁷ The diet allowed children to reduce their medication burden (patients averaged having 6.2 anticonvulsant medications before the trial), and proved to be more effective than many medications. More studies in larger patient populations are needed over longer periods of time to make stronger conclusions.

Research attributes the ketogenic diet’s anticonvulsant properties to an increased seizure threshold. Mitochondria in the brain have healthier biogenesis and density, leading to increased resistance to metabolic stress.²⁸ Another way the diet increases seizure threshold is through decreased glucose consumption and production of glycolytic ATP.²⁸ Subsequently, potassium channels remain open and hyperpolarize the neuronal membrane.²⁸

Researchers have found that ketone bodies produced from fatty acid oxidation have their own anticonvulsant effects. Although different ketone bodies have different effects, researchers have found that they can alter various neuronal membrane transporters to decrease excitability. Ketone bodies can inhibit transporters like the vesicular glutamate transporter and neuronal potassium channels. Inhibition of these transporters prevents signal transmission and causes decreased excitability of neuronal cells.²⁹

Other Neurodegenerative Disorders

In addition to epilepsy, promising evidence shows that the ketogenic diet has favorable effects for other neurodegenerative disorders. As the incidence of Alzheimer’s disease (AD) increases, few treatment options are available. The ketogenic diet may reduce deposition of amyloid beta (Aβ) plaques in patients with AD. With the addition of D-β-hydroxybutyrate (an enantiomer of the ketone body 3HB) to the ketogenic diet, ketones were able to increase neuron survival by reversing Aβ (1-42) toxicity. ³⁰ By increasing ketone production in the liver, the ketogenic diet can reduce the production of reactive oxygen species.³¹ Ketone bodies also work to block histone hyper-acetylation initiated by histone deacetylases (HDACs), increasing antioxidant levels. The ketogenic diet can improve metabolic efficiency which improves ATP concentrations resulting in further protective effects.³¹

Ketones’ neuroprotective effects can potentially help patients with Parkinson’s disease by reducing oxidative stress, maintaining energy supply, and modulating deacetylation and inflammatory responses.^31,32 Because they can reduce inflammation and inhibit the glutamate excitatory synapse, infusions of ketone bodies like 3HB may lead to small improvements in Parkinson’s symptoms.³² The use of the ketogenic diet for Parkinson’s is still controversial, thus further research is necessary.

Glaucoma

Glaucoma is the second leading cause of vision loss in the world.³³ Because ketone bodies are the major source of energy when participating in the ketogenic diet, mitochondrial dysfunction in the retina and optic nerves associated with glaucoma may be decreased.^32,34 A 2020 observational study assessed the benefit of the ketogenic diet in 185,638 adults with glaucoma from three studies between 1976 and 2017. Results showed that following a low carbohydrate diet was associated with 20% lower risk of developing primary open-angle glaucoma with initial paracentral visual field loss.³⁵ However, evidence is still lacking, and researchers need to investigate more to prove the ketogenic diet’s efficacy for glaucoma.

Colorectal Cancer

According to the American Cancer Society, colorectal cancer is the third leading cause of cancer-related deaths in men and women in the United States.³⁶ A 2022 study suggests that the ketone body, 3HB, can suppress colorectal cancer.³⁷ In one experiment, investigators evaluated the ability of the ketogenic diet to prevent tumor growth and development in mice.

They discovered that 3HB could suppress tumor growth by reducing proliferation of colonic crypt cells.³⁷ 3HB induced positive changes in tumor growth through the upregulation of the homeodomain-only protein X (HOPX). The HOPX protein inhibits cancer organoid growth when overexpressed.³⁷ Mice fed the ketogenic diet showed elevated levels of HOPX specific to the colonic tissue.

Overall, mice assigned to the ketogenic diet experienced improved long-term survival rates. To test the efficacy of the ketogenic diet for existing tumors, after two cycles of dextran sodium sulfate, researchers introduced the diet to the mice. After exposure to the diet, tumor growth decreased. When researchers discontinued the ketogenic diet from the mice, tumor development proceeded.³⁷

This discovery led to further testing, this time in human organoids. Organoids are tissue cultures derived from stem cells.³⁸ In the right environment, they are used to replicate organs. They are an essential tool to monitor disease development. Findings mimicked the results from the mice in 41 patients with colorectal cancer. This suggests that the ketogenic diet may be used for the prevention and treatment of colorectal cancer in the future.³⁷

PAUSE AND PONDER: How do you think patients would feel using the ketogenic diet as a primary treatment for neurodegenerative diseases in the future?

Contraindications to the Ketogenic Diet

Some patients should not follow the ketogenic diet. It is contraindicated in patients with liver failure, pancreatitis, inborn disorders of fat metabolism, primary carnitine deficiency, carnitine palmitoyl transferase deficiency, carnitine translocase deficiency, porphyria, and pyruvate kinase deficiency.^39,40

Because of the high risk of developing diabetic ketoacidosis (DKA), patients with type 1 diabetes on SGLT2 inhibitors should not participate in the ketogenic diet.⁴¹ DKA occurs when the body produces a dangerously high level of ketones at a rapid pace. Feeling extremely thirsty and frequent urination are early symptoms of DKA. Later symptoms of DKA include dry skin and mouth, flushing, fatigue, stomach upset, and pain. Another notable warning sign of DKA is a fruity odor on the patient’s breath. Acetone is responsible for the sweet scent and indicates high levels of ketones in the body.⁴² If left untreated, DKA can further develop, ultimately leading to death.

Pregnancy is also a contraindication. The CDC recommends 340 additional calories per day during the second trimester of pregnancy and 450 additional calories per day during the third trimester.⁴³ The CDC also recommends a well-balanced diet for women who are expecting. Losing weight during pregnancy is not safe and can be harmful to a patient’s baby.⁴³ Folic acid and iron supplementation is pivotal in a fetus’ development. The World Health Organization recommends daily iron and folic acid supplements to reduce the risk of low birth weight.⁴⁴ If a pregnant woman were to go on the ketogenic diet, she would need to ensure she consumes the suggested dose of 120 mg elemental iron and 2800 µg (2.8 mg) folic acid daily.⁴⁴ Overall, no evidence indicates that the ketogenic diet is safe for pregnant women.

KETOGENIC DIET SAFETY AND COUNSELING

Although several studies suggest the ketogenic diet can be effective for weight loss, limited literature is available concerning its long-term effects. Long-term effects include hepatic steatosis, hypoproteinemia, kidney stones, and vitamin and mineral deficiencies.⁴⁰

Currently, no guidelines address the ketogenic diet specifically, and other guidelines do not include the ketogenic diet for the treatment of the previously mentioned diseases. Researchers must complete longer term studies with larger patient populations to prove the ketogenic diet’s benefits and elucidate any long-term risks. Pharmacists and other healthcare providers should keep this in mind when recommending the diet to patients.

The Keto-Flu

A common adverse effect of the ketogenic diet is the “keto-flu.” The symptoms are indicative of carbohydrate withdrawal that can create symptoms like brain fog, fatigue, nausea, vomiting, constipation, and muscle soreness.^{40, 39} Symptoms usually begin within one to two days and resolve within a week or less. Pharmacists can counsel patients on proper hydration, light exercise, rest, and starting the diet slowly to try to prevent the keto-flu.

Cardiovascular Effects

As research has previously shown, the ketogenic diet shows short-term benefits for obesity and cholesterol. Due to the overconsumption of fats, researchers wondered about the longer-term effects. In rodent studies, the ketogenic diet led to the development of hepatic inflammation and nonalcoholic fatty liver disease.⁴⁵ Limited research has been done for nonalcoholic fatty liver disease in humans and more study is needed.

Other Adverse Effects

While on the ketogenic diet, patients may experience constipation. The healthcare team should implement a bowel regimen for the patient including an agent like polyethylene glycol 3350 (MiraLAX^®) that’s sugar-free, meaning it adds no additional carbs. Other notable side effects are kidney stones and a decrease in bone density. To prevent kidney stone occurrence, pharmacists can counsel patients on drinking large amounts of liquids.. Patients can reach out to their providers to ensure they check bone health routinely. Several advisory groups recommend bone mineral density screening for women aged 65 and older and men aged 70 and older, and for other patients who are at high risk. Patients participating in the ketogenic diet are no exception, and could be considered high-risk if they do not consume enough calcium and vitamin D. Pharmacists can counsel patients to monitor their calcium and vitamin D intake and supplement it if necessary. Upon screening, providers may also recommend calcium and vitamin D supplementation for patients who experience a decline in bone mineral density.⁴⁶

What Can Health Professionals Do?

Pharmacists can counsel patients on ketone testing to prevent occurrences of DKA. When a patient’s blood glucose exceeds 240 mg/dL, testing ketone levels every four to six hours is warranted.⁴⁷ Ketones can be monitored through the urine and blood. A urine stick test is the most common and changes color depending on the ketone level. Although urine tests are convenient, blood ketone tests from finger sticks are more accurate because they measure 3HB and/or AcAc in the blood.⁴⁸ If ketone tests indicate high levels, the patient is at moderate or high risk for ketoacidosis and patients should seek medical attention. Table 2 shows normal ketone levels, the optimal state of nutritional ketosis, and the level for ketoacidosis.

Table 2. Ketone Levels48
Normal Ketone	≤ 0.5 mmol/L
Nutritional Ketosis	1 - 3 mmol/L
Ketoacidosis	≥ 20 mmol/L

Patient adherence to long-term regimens always becomes challenging. Counseling patients on the importance of sticking to their diet and other medications will increase the likelihood of desired results.

PAUSE AND PONDER: On average, how long do you think a patient can remain adherent to the ketogenic diet lifestyle?

Medication management is a vital component of patient safety. To ensure that starting the ketogenic diet is safe, a healthcare professional should perform a complete medication reconciliation. Pharmacists, with an interdisciplinary team, should then develop a plan for medication adjustments (including OTCs) and carbohydrate intake. The use of medication package inserts, institutional databases, and manufacturer helplines can assist the team in determining carbohydrate content of drugs to make the process more seamless.⁴⁶ The following oral suspensions contain high carbohydrate contents:⁴⁹    

• Amoxicillin
• Nystatin
• Levetiracetam
• Midazolam
• Phenobarbital
• Phenytoin
• Baclofen
• Ibuprofen

Making patients aware that they must inform the healthcare team of any new medications is equally as important.

Some medications are of concern with the ketogenic diet.

• Patients taking SGLT2 inhibitors should not participate in nutritional ketosis due to the increased risk of diabetic ketoacidosis.
• Clinicians need to monitor patients taking the anticonvulsant valproate (a fatty acid) and might need to adjust their doses since the ketogenic diet increases metabolic efficiency and valproate can be burned by cells for energy.⁵⁰ Patients may feel as though valproate is not as effective after starting the ketogenic The dose, in this case, may need to be increased temporarily.
• A case study showed that topiramate can increase blood pH, inducing metabolic acidosis and kidney stones.⁵¹ This may become hazardous if patients are already in nutritional ketosis.
• Patients may experience hypotension while taking antihypertensive agents and following the ketogenic They should monitor blood pressure frequently.

Pharmacists and other health professionals should inform patients to stay hydrated to reduce the risk for kidney stones and eat low salt food items.

MYTHS AND FACTS

The ketogenic diet has become increasingly popular over the years. Halle Berry, Vanessa Hudgens, Kourtney and Kim Kardashian are a few of many celebrities that have tried the ketogenic diet and have seen incredible results. MTV’s Jersey Shore star, Vinny Guadagnino, also known as the Keto Guido, is no stranger to the diet and has even written a keto cookbook. Seeing such drastic transformations all over tabloids and social media, without a doubt leaves people wondering “Why not? If they can do it, so can I,” while others think, “This can’t be real.”

 

Many misconceptions create skepticism among patients from the abundance of information available on the internet. Pharmacists can alleviate patient worries by staying informed and referring patients to reliable resources. Table 3 below dispels common myths.

 

Table 3. Myths and Facts About the Ketogenic Diet52
MYTH	FACT
The ketogenic diet is bad for your health.	The ketogenic diet has several health benefits including: ●      Weight loss ●      Improved brain function ●      Reduction of seizures ●      Blood sugar management ●      Improvement of PCOS symptoms Side effects may include nausea, vomiting, constipation, or other common side effects.
All I have to do is consume any type of fat while going keto.	Patients should eat healthy fats like avocados, nuts, seeds, and fish. Healthy fats lower LDL levels and raise HDL levels. Unhealthy fats saturated and trans fatty acids (e.g., fried foods, pastries, butter, and cream) raise LDL levels.
If I go keto, I will get ketoacidosis.	Ketosis and ketoacidosis are different conditions. The ketogenic diet induces ketosis. ●      In ketosis, the body burns fat since carbohydrates are unavailable. Nutritional ketosis is a normal response. ●      Ketoacidosis is a complication seen primarily in patients with T2D where the blood becomes acidic. It can be life-threatening.
I will have no energy if I start a ketogenic diet.	Some people may experience an adjustment period while beginning the ketogenic diet. They may experience temporary fatigue, brain fog, or the “keto-flu.” Eventual ketone production fuels the brain with energy and resolves symptoms.
The ketogenic diet is only useful for weight management.	The ketogenic diet has proven effective in patients with diabetes, PCOS, metabolic syndromes, Alzheimer’s disease, and obesity.
I can’t drink any alcohol while on the ketogenic diet.	Various low-carb alcoholic beverages can be substituted. Light beer, vodka, gin, and rum are a few examples, but patients should keep intake low-moderate. Patients should avoid sweet drinks and cocktails to prevent high sugar intake.

 

Another common misinterpretation is that any low-carbohydrate food is considered keto. No food item has the same benefit as the other. The healthcare team must work with patients to create dietary plans that are more feasible for them. With a tailored diet plan, patients are more likely to feel structured and reach their goals. Overall, providers should conclude that patient education is necessary to certify patient trust and safety.

 

PATIENT RESOURCES

 

Reliable resources for patients are hard to find. Table 4 describes some resources that pharmacists can provide to patients for more information.

 

Table 4. Resources About the Ketogenic Diet for Patients

Cleveland Health Clinic	-        Discusses what patients eat on the ketogenic diet -        Small tidbits on benefits and risks -        Includes information on populations that could benefit from the diet -        https://health.clevelandclinic.org/what-is-the-keto-diet-and-should-you-try-it/
Harvard University Health	-        Discusses key-takeaways from a ketogenic diet review -        Gives food examples -        Easy-to-understand -        Discusses health implications for certain patient populations -        https://www.health.harvard.edu/blog/ketogenic-diet-is-the-ultimate-low-carb-diet-good-for-you-2017072712089
Academy of Nutrition and Dietetics	-        Popular nutrition website that presents findings on various health topics -        Discusses populations that the ketogenic diet would not be safe in -        Gives background on the diet -        https://www.eatright.org/health/wellness/fad-diets/what-is-the-ketogenic-diet
Everyday Health	-        Discusses risks and benefits of the diet -        Provides food substitutions and daily meal plans -        Discussion potential supplements and vitamins that may be beneficial to dieters -        Discusses other nutrition techniques for other topics -        Articles are peer-reviewed -        https://www.everydayhealth.com/diet-nutrition/ketogenic-diet/comprehensive-ketogenic-diet-food-list-follow/
EatingWell	-        Brief explanation about the ketogenic diet -        Provides variety of food options for dieters -        Easy-to-understand and discusses other nutrition techniques -        Peer reviewed and gives background on all authors/editors -        https://www.eatingwell.com/article/290697/ketogenic-diet-101-a-beginners-guide/

 

 

CONCLUSION

Following a low-carbohydrate, high fat diet that uses ketone production to fuel the body requires a large selection of foods if patients are to maintain this diet. This is the challenge of the ketogenic diet. Pharmacists and technicians need a good understanding of what this diet is—and what it is not—so they know when prescribers are likely to use it for diseases. Pharmacists, as they screen for contraindications, should identify the signs of ketosis and counsel patients on managing safe ketone levels.

Patient education is the key to reaching patient goals. Pharmacists must be ready to address patient questions and concerns regarding the ketogenic diet in conjunction with current medications. When pharmacists are a part of the care process, outcomes improve.

 

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