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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.

 

Download CE Activity

INTRODUCTION

Fad diets have always existed but have been on the rise in recent years due to the explosion of social media in the 21^st Century. A fad diet is a popular diet followed to achieve fast results or fix long-term problems associated with eating, specifically weight.¹ Fad diets are labeled as fads for a reason. These short-lived trends with wide popularity disregard for the rationale behind or quality of the approach itself.^3,4

People who choose fad diets are often trying to fix ongoing problems including overweight or obesity, inadequate nutrition, sedentary behaviors, and failure to maintain overall healthy habits.² Individuals who follow fad diets adhere to a mainstream concept of dieting without acknowledging individual health needs and restrictions. Health consequences may arise as a result of adhering to a diet ill-suited to an individual's nutritional needs and ability to sustain the associated effort. In addition, certain diets may influence medication interactions and disease outcomes. For this reason, fad diets can undermine patient safety.

 

This continuing education activity summarizes popular fad diets to inform pharmacy teams of their benefits and risks. It will allow teams to make recommendations for patients, understand how medications interact with the diets, and help prevent health complications.

 

The History of Fad Diets

Fad diets have existed throughout history in different forms. For example, in the 1920s, the Cigarette Diet was popular. Lucky Strike, a cigarette company, promoted the cigarette diet. They claimed that cigarettes would suppress appetite to boost sales using the tagline “Reach for a Lucky instead of a sweet.” Promoters advertised that people would lose weight successfully while following the diet.⁶ The 1940s saw the rise of the Master Cleanse. This juice cleanse consisted of a meal replacement drink consisting of hot water, lemon juice, maple syrup, and cayenne pepper. Its popularity stemmed from promises of cleansing the body of toxins while providing very few calories. It reached new levels of popularity in 2006, when superstar Beyoncé claimed to lose 20 pounds in two weeks using this method ⁶ In the 1960s, The Drinking Man’s Diet made an appearance. The recommendation was to consume high-protein and low-carbohydrate foods while drinking as much alcohol as desired. An example meal may have included a large serving of steak, salad or vegetables, and several alcoholic beverages. The Drinking Man’s Diet’s supporters considered alcohol a good carbohydrate and allowed indulgence. This diet was marketed toward the male population.⁶

 

People have always been interested in quick fixes for weight loss and appearance without considering how they will feel or how to keep the weight off indefinitely.¹ This approach to choosing a diet or making nutrition decisions ignores tactics that sustain weight loss. Fad diets are inherently unsustainable options that often lead to weight regain. These outcomes prove many fad diets are unreliable (if not dangerous).

 

With the creation and explosion of modern social media in the early 2000s, fad diets surged in popularity. Social media often fosters a community of misinformation regarding fad diet composition, how to follow the specific diet, and the diet’s benefits.⁵ Much of the information on social media regarding fad diets lacks reputable, verifiable sources. Fad diet promoters use scientific jargon loosely and inappropriately to make information convincing when describing seemingly miraculous diets. However, the information could just be the opinion of an individual or a promotional company sponsorship.⁵ Unless diet information is published by a credible source, it should be regarded as untrustworthy.

 

Pause and Ponder: How many times a week do you see diet-related content on social media?

 

Fad Diet Prevalence

Approximately 45 million Americans (about 14% of the total population) go on a diet each year.⁷ Of these diets, 50% are fad diets.⁷ According to the United States (U.S.) Weight Loss & Diet Control Market, the weight loss industry is one of the most advertised with investors spending $66 billion annually.⁷ More people than ever are overweight or obese and using diets as a solution. Table 1 summarizes obesity’s prevalence, which is rising each year in the U.S.

 

Table 1. Obesity Prevalence in the U.S. Population⁸

Age (years)	% of Population
Adults aged 20 and up	41.9%
Adolescents aged 12-19	22.9%
Children aged 6-11	20.7%
Children aged 2-5	12.7%

 

According to the Centers for Disease Control and Prevention (CDC), individuals who are overweight or have obesity are at elevated risk for many health issues. These include elevated cholesterol, stroke, heart disease, hypertension, cancer, type 2 diabetes, mental illness, low quality of life, and mortality, among others.⁹ While many factors can influence weight, individuals can adapt their diets to meet nutritional needs and make long-term differences to improve health outcomes.

 

TYPES OF FAD DIETS

As the definition implies, fad diets’ popularity increases and decreases with current trends. This section discusses some of the most popular current fad diets.

 

Intermittent Fasting

Individuals following an intermittent fasting diet alternate eating and fasting (not eating or drinking anything) on a cyclic schedule. This diet focuses more on eating during specific periods of time than restricting meal components. Various intermittent fasting schedules exist, but popular versions include alternate-day and time-restricted fasting.^10,11 Alternate-day fasting means fasting every other day, while time-restricted fasting involves eating within set time windows during the day. Individuals should consult a doctor and choose the type of intermittent fasting that best fits their health needs (but most do not). Studies show following intermittent fasting schedules leads to decreased body weight, body mass index (BMI), and waist circumference.¹¹ Studies also show improved blood glucose and triglyceride levels following this diet.¹⁰

 

The body uses ingested calories—specifically carbohydrates, sugars, and nutrients—as fuel.¹⁰ If people eat continuously throughout the day, the body uses ingested calories as fuel to perform necessary bodily functions. The body stores unused ingested calories in the form of fat where they become an energy reserve.^10,12

 

When the period between meals lengthens and the body lacks a constant supply of calories for fuel, it turns to the fat reserve to burn fat stored in the body. The theory is that the longer a person goes without eating, the more the body will use its fuel reserve. The more reserve is used, the more fat is burned.¹⁰ As more of the reserve is used for energy while intermittent fasting, more weight is lost through fat burn.

 

Intermittent fasting regulates eating times without restricting foods or food groups. Dieters must make conscious choices to include foods beneficial to health. This includes fruits, vegetables, plant proteins or lean meats, whole grains, superfoods (see Sidebar: Superfoods), and low-fat dairy options.¹² Healthy choices also include limiting processed foods and sugars.

 

Sidebar: Superfoods¹³

Superfoods are nutrient-rich and high in important dietary components including antioxidants, vitamins, minerals, fiber, and healthy fats. These help keep the body functioning, reduce disease risk, and improve well-being. Some examples of superfoods are

• Avocados → These include potassium and healthy fats to lower the risk of heart disease.
• Chia seeds → These include fiber, protein, antioxidants, vitamins, and minerals. They are also easy to add to recipes.
• Dark and leafy greens → All greens are good greens, but these are especially nutrient dense, including vitamins A, C, and E. They also contain vitamin K, which promotes bone health.
• Ginger → This includes vitamin C, magnesium, and potassium. It also helps reduce pain and aid nausea.
• Salmon → Fish is high in omega-3 fatty acids, which can help reduce heart disease.
• Yogurt → This includes calcium and protein to help with bone health, cancer prevention, and immune health. It is also a good source of probiotics to support gut health.

 

Pause and Ponder: Do patients ask about superfoods when discussing dietary information or supplements? Do you know which to recommend?

 

Pros and Cons

Like most diets, intermittent fasting has benefits and drawbacks. Following intermittent fasting correctly boosts memory, improves blood pressure, induces fat loss while maintaining muscle mass, helps prevent obesity, improves type 2 diabetes by reducing insulin resistance, and improves tissue health.^12,14 Intermittent fasting also regulates the body’s 24-hour cycle to improve physiological functioning and metabolic health. As a result, gastrointestinal (GI) microbiomes, energy levels, and sleep may improve.¹⁵

 

Drawbacks of this diet include issues with long-term maintenance/adherence, leading to regaining weight.¹⁰ It is difficult and tiring for individuals to maintain fasting for extended periods. In addition, until the body is accustomed to fasting periods, symptoms such as headaches, nausea, or dizziness may occur. Some individuals may feel an initial decrease in energy levels when starting this diet.¹⁰

 

Keto Diet

The keto diet, also known as the ketogenic diet, is centered around depriving the body of carbohydrates.¹⁶ Researchers originally developed the ketogenic or keto diet in the 1920s as an epilepsy treatment, especially for resistant pediatric cases.¹⁷ The rise of effective antiepileptic drugs and treatments decreased use of the ketogenic diet for this purpose. As originally designed, total daily calories were composed of high fat intake (70% to 80%), moderate amounts of protein (10% to 20%), and low carbohydrate intake (5% to 10%).¹⁶ An iteration of this diet has gained more traction since the 1990s, as people realized its effectiveness for quick weight loss.¹⁶

 

The keto diet helps with weight loss through the processes of gluconeogenesis and ketogenesis. Under normal circumstances, carbohydrates produce energy for the body.¹⁶ When insufficient carbohydrates are available, insulin secretion is reduced and glucose is less available. The body then exploits gluconeogenesis, using lactic acid, glycerol, and amino acids to produce glucose as an energy source.¹⁶

 

If carbohydrate levels drop further, the body enters ketogenesis and secretes ketone bodies as an alternative energy source.¹⁶ As insulin secretion levels remain low and ketone bodies are used for energy, fat and glucose storage falls significantly. This can cause other fats to break down, leading to bodily fat loss.¹⁶

 

To remain in ketogenesis, the body needs constant carbohydrate deprivation.¹⁶ The longer it is deprived of carbohydrates, the more fat is burned in the ketotic state. This is known as nutritional ketosis and is considered safe, as opposed to the metabolic state of ketoacidosis (an accumulation of ketones that increases the blood’s acidity), which can be life-threatening.¹⁶

 

During ketoacidosis, ketone bodies are produced in large amounts and can acidify the blood pH.¹⁶ Acidic blood pH reduces the amount of oxygen blood delivers to cells leading to cell death and life-threatening complications. Insulin keeps the production of ketone bodies at bay, so sometimes people with type 1 diabetes develop ketoacidosis due to decreased insulin production. Taking diabetes-related medication correctly reduces the risk of ketoacidosis in people with diabetes. Following a low carbohydrate diet for a prolonged amount of time can also lead to ketoacidosis.¹⁷ To reiterate, ketogenesis is the production of ketone bodies in response to carbohydrate and glucose depletion. Low concentrations of ketone bodies are generally regarded as a safe, as opposed to high concentrations caused by ketoacidosis (which is a medical emergency).¹⁶

 

What to Eat and Avoid

Given the strong emphasis on high-fat foods, healthy fats comprise the largest part of this diet.¹⁶ Foods such as seeds and nuts, coconut, avocados, poultry fat, and plant fats (e.g., olive or coconut oils) are encouraged. In addition, some dairy products—including butter, hard cheese, and yogurt—are allowed, but people on a ketogenic diet should avoid cream, ice cream, and full-fat milk given their natural sugar content.¹⁷ Individuals following this diet should consume a moderate amount of protein, ideally meats high in omega-3 fats.¹⁶ This includes grass-fed beef, free-range poultry, wild-caught fish, and pork. Nuts, seeds, tofu, and eggs are also acceptable protein sources.¹⁷

 

Adhering to a diet with less than 10% of calories from carbohydrates can be challenging, especially since this diet requires individuals to calculate “net carbs” (See Sidebar: What are “Net Carbs”?).¹⁶ Vegetables lacking high starch contents (e.g., cauliflower, broccoli, onions, leafy greens, bell peppers, garlic, mushrooms, cucumber, summer squash) are encouraged. Small portions of fruit are also allowed, and fruits with a lower net carb content (e.g., berries) are preferred. Other acceptable carbohydrates include dark chocolate, herbs, spices, unsweetened tea, coffee, vinegars, and mustards.¹⁷

 

 

Sidebar: What are “Net Carbs”? ¹⁷

The body cannot digest or metabolize some carbohydrates because of their molecular structures. For example, fruits, vegetables, whole grains, and sugar alcohols contain insoluble fibers that are indigestible. Insoluble carbs have no energy value or blood sugar impact, so they are allowed when following the keto diet. The keto diet requires dieters to calculate “net carbs,” the amount of carbohydrates taken in by the body that are digested and metabolized and thus contribute to calories. However, it is important to note that the total calorie level does not change even when “net carbs” are calculated.

 

Individuals calculate net carbs by subtracting the number of ingestible carbohydrates from the food’s total amount of carbohydrates. For example, food containing 24 total carbohydrates and 21 ingestible carbohydrates equals 3 net carbs. Ingestible carbohydrates can typically be found by subtracting the amount of fiber from the amount of carbohydrates in the food item, but it can be more complicated. A number on online net carb calculators are available to help.

 

Net carbs are also known as “impact carbs.” Food manufacturers use both terms as marketing strategies, but governing bodies do not regulate use of these phrases.

 

Foods containing added sugar, whole or refined grains, and flour products are restricted.¹⁷ Starchy foods are also not allowed, including some high-starch vegetables such as corn, potatoes, and winter squash. Fruits with a high net carb content and fruit juices are restricted. Most keto programs also advise against alcoholic beverages due to their carbohydrate content and added sweeteners.¹⁷

 

Pros and Cons

The keto diet may be beneficial for weight loss, as it uses ketone bodies for energy to deplete glucose and fat storage abilities. Decreasing sugar intake lowers the risk of developing diabetes, obesity, and metabolic syndrome.¹⁶ Following this diet may reduce cholesterol, blood sugar, and blood pressure, and decrease insulin resistance.¹⁷

 

Diet restrictions may cause short-term adverse effects such as nausea and vomiting, fatigue, headaches, dizziness, and insomnia.¹⁶ This is known as the “keto flu.” Symptoms usually resolve once the body adjusts to the diet after a few weeks. Fluids and electrolyte replenishment can help alleviate discomfort during this period.¹⁶

 

Documented long-term adverse effects include increased uric acid levels in the blood, increased risk of kidney stones, and osteoporosis.¹⁷ This is due to the diet’s restrictive nature and omission of necessary components to sustain a healthy diet. Nutrient deficiencies can occur as a result of following this diet.¹⁷

 

People struggle to adhere to the ketogenic diet due to strict regulation of fat, protein, and carbohydrates.¹⁷ Dieters must carefully monitor their adherence to intake limits and meet target levels. This can be difficult for individuals to maintain long-term and lead to low adherence to the diet.¹⁷

 

Pay-for-Food Systems

Pay-for-food diets are meal prep services or meal delivery services with pre-portioned ingredients, pre-cooked meals, or meal replacement options. Diets focus on weight loss and are designed for convenience. These options take the guesswork out of planning meals and make it easier to track eating.

 

Nutrisystem

The Nutrisystem meal service claims its diets help with weight loss through a high-protein and low glycemic approach.¹⁸ Nutrisystem expects users to lose one to two pounds a week by managing blood sugar and controlling hunger to avoid overindulgence. Dietitians design meals to include healthy options and relieve the stress of planning.¹⁸

 

Meals are pre-portioned to fit an individual’s needs and tastes.¹⁸ The meals’ composition of lean protein, healthy fat, and smart carbohydrate ingredients is supposed to curb hunger. Protein shakes and bars are options to supplement plans. Nutrisystem claims deprivation is too restrictive and allows for some deviation from the plan or healthy alternatives to “bad foods.” In addition, dieters can track their progress and calories using Nutrisystem’s app. This system promotes prizes and special offers to keep individuals motivated.¹⁸

 

Prices vary by plan type but can range from $9.99 to $15.18 a day. Nutrisystem has plans designed specifically for men, women, partners, and people with diabetes.¹⁸

 

SlimFast

When SlimFast originated, the system promoted meal replacement shakes to lose weight.¹⁹ The company has since expanded to include drink mixes, snacks, and meal replacement bars. The products are grouped into categories such as calorie control, high protein, keto, and intermittent fasting. The website also contains a recipe section for dieters to use in their meal planning.¹⁹

 

SlimFast plans are based on individuals’ goals and preferences, including the Favorite Foods Plan, Keto Plan, High Protein/Low Carb Plan, Original Plan, and Intermittent Fasting.¹⁹ Dieters purchase SlimFast products to supplement or replace parts of their current diet. Plans themselves are not priced because individuals buy their own groceries and supplement with SlimFast products associated with the plan of their choice. The company also has an app to use for weight management tracking and a private Facebook group to communicate with other individuals on the diet to offer support or guidance.¹⁹ SlimFast claims their plans and products promote and maintain weight loss and encourage people to make better food choices.¹⁹

 

Jenny Craig

The Jenny Craig company has recently gone out of business after 40 years in the industry. Some experts indicates that one reason has been the availability of weight loss medications and increased competition in this market space. This system emphasized one-on-one coaching mixed with healthy foods to lose weight quickly.²⁰ The company claimed dieters could lose up to 18 pounds in the first four weeks. Coaches designed meal plans to be unrestrictive and included an individual’s favorite foods. Meals focused on low-fat foods with high fiber and protein. This program also emphasized physical activity and occasional intermittent fasting to aid the weight loss process.²⁰

 

Plans consisted of meals from the program, two snacks, and supplemental grocery items daily to promote weight loss and increase metabolism.²⁰ One snack included Jenny Craig’s Recharge Bar, used when intermittent fasting. The program claimed the Recharge Bar helped dieters lose weight faster, feel less hungry, and maintain fasting. Jenny Craig coaches designed plans and provided guidance for the duration of the program.²⁰

 

Food was delivered weekly or biweekly. Depending on the type of plan, individuals paid $13.99 to $21.99 per day. Prices were based on the number of meals, membership length, and amount of coaching support included. Promotional offers and meal bundles were available.²⁰

 

Pros and Cons

Pay-for-food diets can be intriguing as they promote healthy choices, weight loss, and convenience.^18-20  They reduce mental load and stress surrounding dieting by making the choices easier or eliminating the need to choose altogether. Some services also provide support groups or coaches for accountability and guidance. In addition, if dieters can adhere to these plans, meal kits promote portion control and reduce overeating.^18-20

 

A major con associated with these diets and meal kits is adherence. As people lose weight on these diets, they may stop using them, gain weight back, and become discouraged about trying again. This can reverse improved health outcomes.^18-20 Another con is cost. Individuals may be discouraged by the prices associated with pay-for-food systems. The cost may not be viable or sustainable options for all individuals.^18-20  

 

Studies have shown these diets to be ineffective. Attrition rates (percentages of people leaving a program) are 30% or greater, and 37% of dieters who complete programs lose less than 5% of their initial body weight.²¹ Other studies failed to produce significant results for how these pay-for-food diets affect weight loss when compared to educating or counseling individuals on weight.²² High attrition rates and insignificant weight loss results suggest these diets are unsustainable and unreliable.²¹

 

Paleo Diet

The paleo diet goes by many names, including the Paleolithic, caveman, or Stone-Age diet. It consists of (allegedly) eating like humans of the Paleolithic era did, mixed with modern components to supplement the diet. The Paleolithic era occurred from roughly 2.5 million years ago to 1,200 B.C. Diet supporters believe current body function is similar to how it functioned during this era and eating foods available or comparable to this time will improve health.²³ Introduced in 2002 by Dr. Loren Cordain, a scientist specializing in nutrition, this diet has surged in popularity in recent years due to weight loss claims.²⁴

 

Due to disagreements about which foods were available in the Paleolithic era compared with today, many diet plans are dubbed “paleo.” They differ in specific foods allowed. All plans emphasize high protein, healthy fats, low or moderate carbohydrates, low sugar and sodium, and high fiber to meet weight loss goals.²³ The term “paleo” will be used to describe this model. The paleo diet consists of consuming mostly lean meats, fruits, vegetables, nuts, seeds, and fish, in line with what researchers believe was consumed during the Paleolithic age.²³ It also emphasizes reducing intake of dairy, grains, and carbohydrates.²⁵

 

Weight loss can occur through several pathways using the paleo diet. ²³ Like the keto diet, ingesting fewer carbohydrates forces the body to use fat for fuel. In addition, replacing highly processed foods, added sugars, and large amounts of carbohydrates with healthier options can aid weight loss. Eating more protein and less calorically dense food (i.e., few calories in a large volume of food) also helps curb hunger and leave individuals more satisfied.²³

 

Less calorically dense foods—including vegetables, fruits, low-fat or fat-free dairy, and egg whites—can be eaten in larger quantities. These foods help with weight loss as they allow individuals to eat a larger volume and feel full, without ingesting large numbers of calories.²⁶ This reduces snacking and overall food intake.²³

 

Conversely, calorically dense foods are high in calories and eaten in small amounts. These contribute weight gain as individuals who eat a small volume consume high numbers of calories.²⁷ Examples of calorically dense foods include²⁷

• Proteins: fish, beans, eggs, cheese, yogurt, fats including nuts, avocados, nut butters
• Carbohydrates: potatoes, brown rice, whole grains

 

Overall, the paleo diet works by breaking down the diet into basic components and making healthier choices. Cutting out foods leading to high glucose or carbohydrate storage also aids in eating healthier and inducing weight loss.²⁸

 

What to Eat and Avoid

Allowed foods emphasize fresh and healthy choices to remain consistent with foods found in the Paleolithic age.²³ This includes lean meats, fish or shellfish, fruit, vegetables, honey, nuts or seeds, and olive or coconut oils. Frozen fruits and vegetables are allowed as they contain the same nutrients as the fresh variety and may be more convenient. Omega-3 fats are important for the body and can be found in fish, grass-fed beef, avocado, olive oil, some nuts (e.g., walnuts, almonds, pistachios), and seeds. Root vegetables such as cassava and sweet potatoes are highly nutritious and are allowed in moderation.²³

 

Restricted foods have little nutritional value or a high glycemic index unsuitable for the paleo diet.²³ For example, white potatoes and processed foods are off limits. Other restricted foods include whole or refined grains, cereals, refined sugar, refined vegetable oil, legumes, dairy products, alcohol, coffee, and salt. Canola is a refined vegetable oil and is not allowed. Restricted legumes include peanuts, beans, and lentils.²³

 

This diet emphasizes eating healthy and portioning fats, proteins, and carbohydrates to enhance health.²³ Calorie counting and general portion control are deemphasized in this diet. Some plans also allow for “cheat meals” (those consisting of food not beneficial to health) in the early stages of the diet to increase adherence.²³

 

Pros and Cons

Components of this diet including fiber, potassium, and antioxidants aid bodily functions and reduce disease risk. Reducing the intake of highly processed foods with little nutritional value also helps improve overall health.²⁵ Short-term benefits may include weight loss, improved blood pressure and cholesterol levels, and increased insulin sensitivity.²³ One study documented improvements in metabolic levels, specifically glucose control and lipids, in people with diabetes.²⁸

 

Unfortunately, restricting or excluding foods altogether for long periods of time can lead to nutritional deficiencies and health complications. For example, limiting dairy intake leads to deficiencies of calcium, vitamin D, and B vitamins.²³ These deficiencies can increase risk of osteoporosis and bone injuries.²⁴ Dairy-related nutrient deficiencies are not specific to the paleo diet, but can occur due to its food restrictions. Restricting grains in the diet also deprives the body of nutrients, which increases risks of diabetes and heart disease. In addition, increased meat consumption (especially red meat) contributes to saturated fat intake and increases risks of cardiovascular problems and diabetes.²³ It may also be difficult for people to adhere to a diet that restricts certain categories of foods.

 

Atkins Diet

The Atkins diet promotes low carbohydrate intake while allowing as much protein and fat as desired. Robert C. Atkins, a heart specialist, developed this diet in the 1960s as a method for weight loss and maintenance.³⁰ Although it is a low-carb diet, the Atkins program acknowledges that eating right is always better than eating less.³¹ This diet is ever evolving to be current with updated nutritional expertise.³⁰

 

Like the keto diet, Atkins emphasizes low carbohydrate intake of less than 20 g per day to start.³⁰ Unlike the keto diet, consumption of fat and protein is less restricted. Carbohydrates are claimed as the problem without regulating the intake of other food groups. Diet supporters believe the sugars found in carbohydrates cause health issues such as blood sugar imbalances and weight gain.³⁰

 

Hypothetically, eating fewer carbohydrates lowers dietary sugar leading to greater satiety, increased energy, less stored fat, and higher metabolism.³¹ When the body lacks glucose and carbohydrates to use as energy, it turns to fat to keep the body functioning through ketogenesis. The more fat a person burns, the more weight they lose.

 

Fat and protein comprise the remainder of the diet. As carbohydrates are viewed as the source of health issues, intake levels of fat and protein are less restricted. Calorie counting and portion control are unnecessary, besides keeping track of carbohydrate intake to stay below the allowable limit.³⁰

 

The Atkins diet is split into phases with specific allowable limits of carbohydrates (see Table 2). The diet’s phases adjust to reflect changes in body function and weight. As carbohydrate levels fluctuate in each phase, protein and fat levels change to achieve satiety.

 

 

Table 2. Atkins Diet Phases³¹

Phase	Instructions
Phase 1: Induction	3 regular sized meals or 4-5 small meals, vitamins/supplements, 8 oz. glasses of water, 20 g net carbs per day
Phase 2: Ongoing weight loss	Can add net carbs in 5 g increments weekly, vitamins/supplements, 8 oz. glasses of water, no more than 40 g a day after adding extra carbs, introduce Atkins food products
Phase 3: Pre-Maintenance	Maintaining previous stages, can add net carbs in 10 g increments weekly to find the perfect balance until the goal weight is reached, maintain carb intake of goal weight
Phase 4: Maintenance	Maintaining Phase 3 carb level, reducing fat intake as carb intake increases, managing cravings and weight

 

 

While phases differ in carbohydrate intake levels, they include similar food groups overall.³⁰ Allowed foods include vegetables, oils, fats, and protein (e.g., eggs, cheese, fish, meat and poultry). Dieters can introduce berries, nuts, seeds, starchy vegetables, and whole grains in the third phase, provided they are still losing weight. Dieters can also eat Atkins’ commercial selection of products during and after phase two. Most fruits, alcohol, baked goods high in sugar, bread, pasta, and nuts are restricted in phase one. Some fruits and grains are added by phase three.³⁰

 

Pros and Cons

Benefits of the Atkins diet include weight loss; decreased blood pressure; and lower incidence of heart disease, metabolic syndrome, and diabetes.³⁰ This diet can also improve blood sugar and cholesterol levels. These benefits are attributed to low carbohydrate intake and subsequent weight loss.³⁰

 

Reducing carbohydrate intake may initially cause symptoms such as headache, weakness, fatigue, and dizziness.³⁰ Unrestricted fat intake can be unhealthy. In addition, using fat as the body’s energy source for too long may lead to ketoacidosis if dieters misuse the plan.²⁹ Nutrient deficiency can also occur on this diet as a result of restrictions.³⁰

 

Weight loss pursuant to this diet is difficult to maintain due to its deficiencies and restrictive nature. Following the carbohydrate limit for long periods of time is difficult and unsustainable for some people.³⁰ Cardiologists warn this diet puts oxidative stress (disproportionate levels of oxygen reactive species overwhelming the ability of body systems to detoxify them) on organs and can cause serious heart problems or fatal complications.²⁹ Some long-term studies have shown the Atkins diet is no more effective than other fad diets. In addition, these studies show that most people who lost weight while following the Atkins diet regained it.³⁰

 

IMPLICATIONS FOR PHARMACY TEAM

Fad dieting can compromise patient safety, and certain patients are at elevated risk for problems. Pharmacy teams are responsible for advising patients about drug-diet interactions and concerns. Table 3 describes conditions and their associated medications that impact the use of fad diets.

 

Table 3. Implications for Pharmacy Teams^{10,16,23,30,32-40}

Diet	Patient Conditions and Associated Medications That Can Be Contraindications with Diets
Intermittent Fasting	·       Age younger than 18 years ·       Pregnancy or breastfeeding ·       Type 1 diabetes o   Insulin, blood pressure medication, cholesterol-lowering medication ·       History of eating disorder
Keto	·       Diabetes o   Insulin, blood pressure medication, cholesterol-lowering medication ·       Hypoglycemia o   Glucagon or other forms of glucose ·       Pancreatitis o   Pain medication ·       Liver failure ·       Fat metabolism disorders o   Cholesterol-lowering medication ·       Primary carnitine deficiency o   L-carnitine supplements ·       Carnitine palmitoyltransferase deficiency ·       Carnitine translocase deficiency ·       Porphyrias o   Hemin ·       Pyruvate kinase deficiency o   Mitapivat (Pyrukynd), folic acid supplements, iron chelators
Pay-For-Food Systems	·       Contraindications and associated medication will depend if it is an individually designed plan or the service’s version of intermittent fasting, keto, etc.
Paleo	·       Cardiovascular related issues o   Anticoagulants, ACE inhibitors, cholesterol-lowering medications, diuretics, etc. ·       Diabetes o   Insulin, blood pressure medication, cholesterol-lowering medication ·       Nutrient deficiency disorders
Atkins	·       Diabetes o   Insulin, blood pressure medication, cholesterol-lowering medication ·       Taking diuretics o   Thiazide, loop, potassium-sparing diuretics or a mix of types ·       Severe kidney disease o   Blood pressure medication, anemia medication, cholesterol-lowering medication, supplements ·       Pregnancy or breastfeeding

 

Nutritional Myths

As mentioned, misinformation surrounding diets has always existed, and social media has magnified the problem. Some myths are more harmful than others, but knowing the facts is essential to correctly informing others.³² Examples of nutritional myths that pharmacy teams can debunk for their patients are found in Figure 1.

 

 

Dieting is not a one-size-fits-all solution. When pharmacy teams advise patients, they must work with patients to consider health factors . Factors to consider include a patient’s medications, lifestyle choices, and known health issues.³³ Pharmacy teams should advise individuals that fad diets are not necessary and following a generally healthy diet is usually sufficient to lose weight. They should make healthy swaps and find strategies that work best for them as individuals. For example, they can cut back on processed foods, consume more fruits and vegetables, and be conscious of fat or carbohydrate intake to ensure healthy sources. These choices are effective ways to achieve the long-term goals without employing fad diets that promote quick fixes.³³

 

CONCLUSION

Fad diets are undeserving of the positive hype they receive. They are short-term solutions that sometimes work for people looking to lose weight or make changes quickly. However, benefits are outweighed by their unsustainability and poor post-diet maintenance planning. Fad dieting also starts a cycle of yoyo dieting (see Sidebar: Yoyo Dieting). The best option for health is to find strategies that work individually and stick with them. Ditch the fad diets and make long-term healthy choices for better, lasting results.³³

 

Sidebar: Yoyo Dieting

Yoyo dieting, or weight cycling, occurs when people achieve their goal weight through dieting, stop dieting and return to unhealthy habits, gain the weight back, diet again for a period, gain the weight back, and repeat the cycle. Yoyo dieting is not only a conscious choice. Physiological mechanisms related to energy intake and expenditure, genetics affecting weight control processes, and the interaction between genes and the environment also affect the cycle.³⁴

 

Yoyo dieting lacks substantial or sustainable changes to lifestyle or nutrition to keep weight off and instead focuses on quick fixes.³⁴ These quick fixes ultimately fail when weight is regained, and the cycle continues. Most weight lost is gained back within the first two to three years after dieting ceases. However, if dieters keep weight off for two years, the likelihood of gaining it back decreases.³⁵

 

Pause and Ponder: Do you think fad diets are helpful or harmful?

Resources for Pharmacists and Pharmacy Technicians

• CDC Resources - Healthy Weight, Nutrition, and Physical Activity ³⁶
  • https://www.cdc.gov/healthyweight/tools/index.html
• USDA - Healthy Living and Weight ³⁷
  • https://www.nutrition.gov/topics/healthy-living-and-weight

 

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INTRODUCTION

Lifestyle modifications have been the mainstay of weight management for years. We’ve all heard the advice: Exercise more, eat less, limit fried foods and sugary drinks, and the weight should slowly disappear. As the weight comes off, you might have some setbacks but just keep tracking your foods and your success is right around the corner.

 

If only it was that easy!

 

Scroll any social media platform today and search the term, “#ozempicweightloss” and a plethora of joyful testimonials appear. Some videos have reports of people losing 17 pounds in 3 months or 64 pounds in a year with no cravings for food. “I can eat whatever I want!!” cried a satisfied user. It is as if the golden ticket has been found in all the candy bars ever produced and everyone is going to the candy factory!

 

Although the recent media emphasis has been on semaglutide, and the Ozempic product primarily, other glucagon-like peptide-1 (GLP-1) receptor agonists have also been associated with weight loss to varying degrees. This continuing education activity’s primary focus is to clarify misinformation, highlight specific GLP-1s’ risks and benefits when used for weight loss, and answer frequently asked questions.

 

WHAT ARE GLP-1 RECEPTOR AGONISTS?

 

Major breakthroughs in the physiology of the pancreas occurred in the early 1900s.¹ At that time, physiologists thought the nervous system had exclusive control of all bodily functions. That idea changed when two scientists, William Bayliss and Ernest Starling, discovered a chemical compound they named secretin. Released from intestinal mucosa, secretin stimulated the pancreas.² Shortly after the discovery of the hormone insulin in 1921, research being conducted at the time primarily stimulated the pancreas to produce insulin by administering glucose via the intravenous route. However, when glucose was administered orally (allowing nutrients to travel to gastrointestinal areas), insulin levels improved substantially. This observation was known as the incretin effect. As a result, two insulinotropic hormones were later identified as incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) discovered in 1971 and glucagon-like peptide-1 (GLP-1) discovered in 1985.^1,2

 

Analyzing the venom of the Gila monster (Heloderma suspectum) in 1990, endocrinologist Dr. John Eng discovered a peptide that stimulated insulin release from the pancreas.³ Named exendin-4, this peptide was similar in structure and function to GLP-1 found in humans. One problem with GLP-1 was that when it is released into the body, dipeptidyl peptidase-4 (DPP-4). quickly inactivated it. Researchers then developed the DPP-4 inhibitors to allow GLP-1 to remain active for a longer period of time. However, synthetically producing GLP-1 receptor agonists (GLP-1RA) directly has extended the peptide’s life. Initial development resulted in twice daily and then daily administration (half-life of 13 hours) of GLP-1RAs. However, when researchers combined semaglutide with a free fatty acid side chain that was tightly bound to albumin, its half-life was increased substantially. The resultant half-life of 165 hours led to an advantageous injection administration schedule for semaglutide: once weekly.^3,4,5

 

Mechanism of Action

As a class of medications, all GLP-1RAs share common mechanisms of action in the treatment of diabetes: stimulate the pancreas to secrete insulin, suppress the action of glucagon, and decrease gastric emptying.⁴ Scientists previously studied the effects of GLP-1 and noticed that the protein, when injected in rats, decreased appetite quickly.⁵ Once clinicians began using GLP-1RAs to treat diabetes in humans, they also observed weight loss due to decreased appetite, increased feelings of fullness, and reduced caloric consumption.⁴

 

Researchers determined that the brain contained GLP-1 receptors. Weight loss was due to GLP-1RAs ability to travel to these receptors and influence specific areas of the hypothalamus that are key to controlling appetite, calorie consumption, satiety, and body weight.⁴ Among GLP-1RAs, semaglutide and liraglutide stimulate the highest amount of weight loss success.

 

 

Comparison of GLP-1 drugs

 

 

Table 1. GLP-1RAs for Weight Loss

Medication	Dosing	Counseling points	Supplies needed for injection
Semaglutide (Wegovy)	Adult and pediatric patients aged 12 and older, starting dosage at 0.25 mg injected subcutaneously once weekly.   Weeks 1-4: 0.25 mg Weeks 5-8: 0.5 mg Weeks 9-12: 1 mg Weeks 13-16: 1.7 mg Weeks 17 & forward: 2.4 mg maintenance dose once weekly.	If adverse reactions occur during the upward titration period, consider delaying increase in dosage for four weeks.   Consider discontinuing the drug if patients do not lose at least 5% of baseline body weight within 3 months	1 alcohol swab or soap and water   1 gauze pad or cotton ball   1 sharps disposable container for used Wegovy pens
Liraglutide (Saxenda)	Adults and pediatric patients aged 12 and older, starting dosage at 0.6 mg injected subcutaneously once daily. (NOTE: This is a DAILY dose)   Week 1: 0.6 mg Week 2: 1.2 mg Week 3: 1.8 mg Week 4: 2.4 mg Week 5 & forward: 3 mg maintenance dose daily.	If adverse reactions occur during upward titration period, consider delaying dose increase for approximately one additional week.   Patients can continue on maximally tolerated dose if goal weight loss achieved on that dose.	Soap and water   Pen needle: 8 mm (Novofine or NovoTwist)   1 sharps disposable container for pen and needles

 

 

Adverse Drug Reactions and Boxed Warning

GLP-1 agonists all have similar and common gastrointestinal adverse effects (nausea [~15–30%], vomiting [~10-15%], diarrhea [~5-10%], abdominal pain, constipation).^6,7,8 Patients can use some strategies to possibly mitigate these adverse effects^6,7,8:

• Increasing the GLP-1 agonist dose slowly
• Staying hydrated and increasing fiber
• Avoiding high-fat foods and alcohol
• Stopping eating when full (and eating only when hungry)
• Spacing meals appropriately
• Using short-term proton pump inhibitors or H₂ blockers if needed

Patients may also experience headache, fatigue, dyspepsia (gastrointestinal upset), dizziness, abdominal distension, eructation  (burping), hypoglycemia in patients with type 2 diabetes, flatulence, gastroenteritis, and gastroesophageal reflux disease.⁷ Clinicians should evaluate patients for gallbladder disease if cholelithiasis (gallstones) or cholecystitis (an inflamed gall bladder) is suspected.

 

 

Reports of patients experiencing hair loss have surfaced recently from news and social media. Listed as an adverse reaction for Wegovy, but not for Ozempic, the Wegovy dose is much higher for treatment of weight loss.⁹ Some clinicians think that the rapid loss of weight triggers the body to conserve calories consumed for essential functions.⁹ Since patients eat less while taking the medications, their diet may consist of lower amounts of protein and minerals important for hair growth. Clinicians have seen hair growth resume once the body reaches a plateau in weight loss, therefore the loss of hair is not permanent.⁹

These drugs also share a boxed warning for risks of pancreatitis and medullary thyroid carcinoma (cancer in the thyroid gland in its medulla, the calcitonin-producing area), which is rare.⁶ Patients with a personal history of pancreatitis or a personal or family history of medullary thyroid carcinoma must avoid these drugs.⁶

These drugs also required an FDA approved Medication Guide whenever GLP-1RAs are dispensed. Pharmacy technicians can be very helpful to pharmacists if they check the patient’s bag and make sure that the Medication Guide is in it.

 

Recent Shortages of GLP-1 Receptor Agonists

 

The sensation of weight loss success for some has caused serious problems for other patients who have diabetes and are struggling to find medication at local pharmacies. Staff in community-based pharmacy practice are well aware of the semaglutide shortages that have occurred in the past year. Pharmacists and technicians should be able to explain the current drug shortages, adverse reactions, and FDA approved or off-label use to patients and other healthcare providers.

 

“Ozempic face”

 

As social media and now news media have reported the success of dramatic weight loss, some users bemoan weight loss woes associated with use of GLP-1 agonists. The term, “Ozempic face,” introduced by a dermatologist in New York, describes the typical female patient who has lost a significant amount of weight on semaglutide but now needs (or wants) dermal fillers for her sagging facial structures.¹⁰ Patients complain about sagging skin and a gaunt appearance, two problems that follow the loss of facial fat after any harsh weight loss.

 

Facial fat loss is common when patients lose weight, and when the weight loss is significant, patients will look older. Skin wrinkles and loosens—hallmarks of aging. Similar to weight loss from old-fashioned dieting, fat loss while taking GLP-1 agonists affects the entire body (not just the face). But patients on GLP-1 agonists for cosmetic weight loss fail to understand that they can’t just lose weight where they’d like to lose weight. The facial fat loss is distressing to them.¹⁰ Pharmacy teams need to know that “Ozempic face” is a slang term, and GLP-1 agonists don’t specifically target the face.¹¹

 

 

Weight Loss Blockbuster or Fad

 

Over the past two years, celebrities and social media influencers have posted successful weight loss stories while using semaglutide and as a result, catapulted its popularity as a weight loss miracle.¹² Questions remain as to how long the weight loss effect will last and if patients will gain the weight back once stopping the treatment. Novo Nordisk, semaglutide’s manufacturer, indicates weight loss can be sustained with long-term use. However, the data collected is limited by a time span of two to three years. Since people who pay out-of-pocket for semaglutide will pay around $1200 per month and some insurance companies may not cover the medication, pharmacists should counsel patients that once the medication is discontinued, weight gain is likely to occur and the weight gain might exceed the original amount lost.¹²

 

 

FDA APPROVED AND OFF-LABEL USE

In December of 2017, the FDA approved semaglutide (Ozempic) for the treatment of diabetes. As significant weight loss was observed, the Semaglutide Treatment Effect in People with obesity (STEP) studies produced promising weight loss data.¹³ As a result, the FDA approved semaglutide for an additional indication, weight loss, in June 2021 under the brand name Wegovy.

 

 

Diabetes

In patients with type 2 diabetes mellitus (T2DM), semaglutide is used in combination with diet and exercise to reduce blood sugar levels.¹⁴ In patients with T2DM who additionally have established cardiovascular disease, liraglutide and semaglutide are indicated to help lessen the risk of major cardiovascular incidents. Dulaglutide, liraglutide, and semaglutide also have beneficial effects on chronic and diabetic kidney disease.⁶ Patients who have a history of pancreatitis should avoid any member of the GLP-1RA class and they are not to be used as treatment for patients who have type 1 diabetes.

 

Dosing semaglutide for the treatment of diabetes requires a period of time for dosage escalation to minimize adverse effects. The FDA has approved both subcutaneous and oral semaglutide (Rybelsus) dosage forms, but only the injectable version is approved for weight loss. Subcutaneously, semaglutide is initially dosed at 0.25 mg once weekly, and after four weeks the patient should increase to 0.5 mg weekly for four weeks. Doses of 1 mg and 2 mg are optional if glycemic control has not been achieved, however the 1 mg dose should also be used for a minimum of four weeks before increasing to the maximum 2 mg strength.⁶ Dosed on the same day of the week, injections can be dosed at any time of the day with or without regard to meals. Patients sometimes miss or forget their scheduled dosing day. If this occurs, patients should inject the dose within 5 days of the missed dose.⁶

 

Patients who have diabetes and currently use metformin, sulfonylureas, thiazolidinediones, or insulin can use semaglutide in combination.  However, patients can administer semaglutide and insulin injections at the same time and in the same areas of the body, but not close together; they must never mix them together in the same syringe.¹⁴ Hypoglycemic episodes are possible when using a sulfonylurea and/or insulin with semaglutide. Pharmacists therefore should remind patients of the signs and symptoms of hypoglycemia when these drugs are used together. Prescribers may need to adjust the dose of insulin and/or a sulfonylurea when starting semaglutide.⁶

 

Obesity and Weight Management

Affecting 70% of American adults, obesity and being overweight contribute to a variety of complications and have reduced quality of life.¹⁵ Debilitating and expensive disease states associated with obesity include: T2DM, cardiovascular disease, osteoarthritis, sleep apnea and cancer.^13,15 Since obesity has roughly tripled worldwide from 1975 to 2016, investigating the reasons for the rise in prevalence and finding solutions is of utmost importance to prevent and treat obesity.¹⁶

 

The access and ease of inexpensive prepared high caloric foods, limited physical activity, and sedentary life styles are factors that have contributed to the rise of obesity.¹⁷ As mentioned, treatment typically has concentrated around the modification of these lifestyle habits.¹⁸ Although the weight reduction is usually moderate in magnitude, it is recovered over time (yes, that means that people gain the weight back!).¹³

 

Anti-obesity medications have been added to lifestyle modifications. Discouraged by adverse drug reactions, contraindications, cost, and moderate weight loss results with weight that is regained over time, many patients and prescribers are hesitant to consider these treatment options.¹⁶

 

Maintaining weight loss has proved equally difficult due to the regulatory centers in the brain that control appetite. Increased hunger and abnormal satiety signals controlled by neuroendocrine pathways have been discovered in the hypothalamus.¹⁶ Researchers have also identified levels of hormones that regulate weight in the hypothalamus. These hormones (leptin, ghrelin, peptide YY, and GIP) play a role in counteracting weight loss after dieting and lead to regain of weight.^{17, 16}

 

Once semaglutide was approved for the treatment of diabetes, clinical trials focused on weight loss. The STEP trials were phase 3 studies implemented to evaluate the safety and efficacy of semaglutide 2.4 mg subcutaneously once weekly injections for 68 weeks. Patients enrolled in the studies were adults with obesity or overweight, a mean age of 46.2 to 55.3 years, mean BMI of 35.7 to 38.5 kg/m², and were mostly female (mean: 74.1% to 81.0%) for five of the trials.¹³All studies included lifestyle interventions at varied intensities.^{13, 18} In one of the larger studies that compared semaglutide with placebo, semaglutide was associated with a 12.4% loss of body weight.¹⁵As a result of the  ≥ 5% in weight loss exhibited in the studies, the FDA approved semaglutide for chronic weight management.^18,15 The approval came in June of 2021, and the manufacturer marketed semaglutide as Wegovy.

 

The STEP 8 trial compared once-weekly semaglutide to once-daily liraglutide and enrolled 338 adult patients with 126 receiving semaglutide 2.4 mg, and 127 participants receiving liraglutide 3 mg. Participants were overweight or obese, without diabetes, had a mean BMI of 37.5, and most had 0-2 comorbidities with dyslipidemia and hypertension being the most frequent.^{19, 18} The primary results at 68 weeks reported an estimated mean change in body weight at -15.8% with semaglutide, and -6.8% with liraglutide.¹⁹ Based on data from this STEP study, the researchers concluded semaglutide is far superior to liraglutide when used for weight loss and had significantly improved cardiometabolic risk factors.^{19, 18}

 

The most frequent adverse side effects reported in the STEP studies were gastrointestinal disorders. Most gastrointestinal side effects were considered mild or moderate in severity and usually were most prominent during the dose titration phase.¹⁹ In the STEP 8 study, semaglutide (84.1%) reported a higher occurrence of gastrointestinal events than liraglutide (82.7%).¹⁹  Other side effects reported were hypoglycemia, acute pancreatitis, gallbladder disorders that generally resulted in cholelithiasis (gall stones), malignant neoplasms (cancer), change in pulse and injection site reactions.^{18, 19}

 

SIDEBAR: Alcohol use disorder potential

As patient use of semaglutide has expanded over the past several years, a side effect has emerged that is surprising many clinicians. Patients have reported an abrupt loss in the desire to drink alcohol, almost to the point of repulsion for some patients. GLP-1RAs are known to decrease the desire, enjoyment, and consumption of fatty foods in humans, but observations that patients began to decrease alcohol consumption was unexpected. Although studies to date have observed a reduction of alcohol in rats, mice, and monkeys when receiving GLP-1RAs, reliable researchers avoid extrapolating results from animal studies directly to humans, especially since humans tend to consume more alcohol than animals.²⁰ Since several patients have reported decreased intake of alcohol and data from animal models reflect these results, researchers are starting to investigate GLP-1RAs effect on patients who have alcohol use disorder (AUD).

 

Existing studies on GLP-1RAs effect on AUD in humans are minimal. A recent study published from Denmark compared the use of a different GLP-1RA, exenatide 2 mg versus placebo in patients with AUD. Researchers were looking to determine if exenatide reduced the amount of heavy drinking days. At the same time, functional MRI brain scans were also completed during the study that focused on areas involved in addiction and reward centers of the brain. Administered once weekly to 127 patients along with cognitive behavior therapy for 26 weeks, exenatide failed to show a decrease in heavy drinking days.²¹  However, in a subgroup of obese patients (BMI > 30 kg/m²) heavy drinking days and total alcohol intake was reduced.²¹ Brain scans revealed weakened alcohol cue reactivity and lower dopamine transporter availability for those patients in the exenatide group.²¹

 

Ongoing phase two clinical trials are studying the effects of semaglutide on patients with AUD.²² Since semaglutide usage and availability have increased with approved indications for diabetes and obesity, researchers are continuing to investigate this drug class for potential promising new therapies.

 

Product information

When used for chronic weight management, semaglutide (Wegovy) is approved in addition to a reduced calorie diet and increased physical activity.^{7, 15} Semaglutide is indicated for patients who meet one of the following criteria: BMI of 30 kg/m² or greater, or patients who have a BMI of 27 kg/m² with at least one comorbid weight related condition (cancer, cardiac disease, diabetes, dyslipidemia, obstructive sleep apnea).^{7, 15} Available in a prefilled pen that contains one dose, semaglutide is a clear and colorless liquid that can be injected into the upper arm, lower stomach or upper thigh.⁷ Semaglutide should be stored in the refrigerator between 36°F to 46°F (2°C to 8°C).⁷ If the pen has been frozen, exposed to light, or heat above 86°F (30°C), the pen should be discarded. The pen remains stable and active for 28 days once removed from refrigeration. Each pen contains the exact dose to be delivered with the needle located inside each pen, therefore each pen should be disposed of in a sharps container.⁷

 

 

Drug shortages, alternatives for therapy

Shortly after marketing Wegovy, the facility hired by Novo Nordisk to fill syringes was cited by the FDA for issues with current good manufacturing processes.^{23, 24} As a result, deliveries and manufacturing of Wegovy was halted in December of 2021.²⁴ At the same time, staggering demand for the drug was reported by the manufacturer mainly due to news and social media platforms announcing the success of several celebrity weight loss stories. As a result of the Wegovy shortage, prescribers started to write for Ozempic off label in an effort to treat obesity and therefore depleted the supplies of Ozempic.²⁴ At the end of 2022 and early 2023, Novo Nordisk announced that supply issue resolution for Wegovy was on the horizon and that production of the drug was being increased. Due to residual and increasing demand though, some supply issues might continue sporadically but over time distribution centers and pharmacies should receive more drug product in the months ahead.²⁵

 

CONCLUSION

Probably the first drug to be considered a social media sensation, semaglutide’s entrance into the realm of prescription weight loss treatments has been filled with anticipation, fame, demand, intrigue, and acceptance. Lifestyle management will continue to play a role in losing and maintaining weight loss, with or without a GLP-1RA used in treatment for weight management. Long term use of semaglutide seems to be necessary to maintain a healthy weight but more research is necessary. Gastrointestinal side effects are seen as the most prevalent adverse effect, leading some patients to discontinue the drug. As availability of semaglutide increases due to resolution of the issues that halted production, price, and lack of coverage by insurance plans continues to be problematic for some patients. This is an area where pharmacy technicians can help by looking for coupons or patient assistance programs.

 

Researchers continue to investigate the various effects seen as a result of usage of semaglutide. Investigators are hopeful of finding new treatments for patients that are struggling with alcohol use disorder and addictive behaviors. GLP-1RAs will continue to be in the headlines for years to come. Pharmacists and technicians hold the golden ticket of information by helping patients and providers understand this unique class of medication’s history, mechanism of action, dosing, side effects, storage requirements, pricing and potential treatments being investigated.

 

 

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INTRODUCTION

Pharmacists and pharmacy technicians strive to provide safe, high-quality care to people when they are unwell, but sometimes we make errors. No one likes to make an error, and in our field, errors can have devastating consequences: preventable illness and injury, unnecessary hospitalizations, disability, and sometimes even death. Experts who have extrapolated data indicate that medical errors now account for 9.5% of all deaths in the United States, which if true, would make medical mistakes the third leading cause of death after heart disease and cancer.¹

Addressing issues systemically has become commonplace in healthcare systems. Most of us know that the first step in resolving medication errors is being able to identify where errors occur and factors that contribute to their occurrence. Tracking in this way allows us to integrate preventive measures into our systems and habits to reduce future occurrence. It’s also important to create safe workplace environments so individuals involved in errors are not afraid to address future errors.²

But external factors aren’t the sole cause of medication errors. Psychosocial and cognitive factors can seriously impact the rates at which errors occur. Individuals who identify their own habits or knowledge gaps that might contribute to errors can take the next step: working on improving.

Definitions of “Medication Error”

To identify and prevent medication errors properly, having a clear, unambiguous definition would be ideal. Unfortunately, everyone seems to use similar—but different—definitions. Each person has a role and individual actions impact the team’s overall performance. Let’s compare a few definitions:

 

An error is a failure to complete a planned action as intended or the use of an incorrect plan of action to achieve a specific endpoint. Bad judgment, ignorance, or inattention might cause this type of error. A pharmacy situation might be when a technician fails to remove expired, very expensive medication and order new stock. When a new patient is admitted to the hospital and needs the medication immediately, the pharmacist hurries to process the order. Assuming that all medication in stock is in-date, the pharmacist approves an intravenous (IV) bag. At final verification, the pharmacist finally notices the medication’s expiration date. With no in-date stock, the pharmacist cannot send the IV. This mistake disrupts patient care. The pharmacy technician failed to keep the inventory in-date and the pharmacist assumed, failed to pay attention, and didn’t double check before proceeding.

 

An error is the enactment of a misconception due to incorrect information or part of a statement that is incorrect. An example in pharmacy might be when a doctor sends a new prescription with a higher-than-expected quantity, fails to update the prescription signatura (sig) or instructions, but tells the patient to take a higher dose. The puzzled pharmacist proceeds to process it. The insurance rejects the claim highlighting the calculated days-supply did not match the quantity indicated. While the pharmacist works on the prescription, the patient comes to the pharmacy to pick up her prescription. The pharmacist cannot contact the doctor who wrote the prescription and the doctor’s colleagues cannot confirm the prescription because they are unsure. The pharmacist decides to dispense a lower quantity per the old instructions so that the insurance will approve it. With the prescription now approved, the pharmacist dispenses the prescription but because the patient follows the doctor’s verbal directions, she runs out sooner than indicated on the prescription. She returns a few days later demanding more. The patient must now contact the insurance, the doctor, and the pharmacist to obtain the prescription that she needs. This could have been avoided if the doctor had noted that the patient would be taking the same drug at an increased dose.

 

An error is the departure from what is ethically acceptable or an incorrect result produced by automation. As healthcare systems increase their use of electronic health records, this problem is  increasing. Most systems are programmed to increase efficiency with the autofill function—meaning the computer will fill a field automatically based on the most common entry—which can increase avoidable errors. Too often, healthcare personnel blindly accept the computer-generated entry or calculations. This can result in a patient being given too much or too little drug and disrupt the quality of care.

 

In summary, medication errors occur in many ways (see Table 1). When a medication error occurs, it reduces the chances of achieving a desired outcome and the margin of safety associated with that outcome. Some medication errors result in adverse drug reactions but many do not. This is because not all adverse events cause adverse drug reactions.³ Many of us have made errors that serendipitously improved something. For example, a person making carrot soup may misread the words “1 garlic clove” and “1 teaspoon of cloves.” The soup will be different—and possibly better—than if the cook used garlic cloves. In medicine, however, errors are rarely “Happy Accidents” and we need to make every effort to reduce and eliminate them.

 

Table 1. Definition of Medication Errors

• A misconception resulting from incorrect information
• A wrong action attributable to bad judgment or ignorance or inattention
• Departure from what is ethically acceptable
• Inadvertent incorrectness
• Part of a statement that is not correct
• The occurrence of an incorrect result produced by a computer
• Unintentional failures to act or plan (when it’s intentional, it’s a violation, not an error)

Source: Reference 3

Systemic Failures: Avoiding Blame

Many healthcare systems and providers now stress approaches that analyze errors as systemic failures. Systems, by nature, are interrelated units that work together toward the same goal. Most medication errors occur as a result of multiple, compounding events—or collapse of a faulty system—rather than an individual’s isolated act.^4,5 It’s amazing how many times a serious error occurs because employees missed the opportunity to catch and rectify an error at multiple points in the patient’s care. Using a systems approach^4,6

• avoids assigning blame
• explores relationships between various parts of the system, and
• recognizes that cause and effect may be separated by space or time.

 

Many experts describe systemic failure using a Swiss cheese analogy. The holes in Swiss cheese represent the faults within a system. If an error passes through one of the holes in one slice of Swiss cheese, one would hope that the holes of the next slice of cheese won’t align, blocking the error. If the holes of the Swiss cheese slices all align, that medication error would slip through and reach the patient. Recognizing the placement of each slice—or the placement of each healthcare professional and that professional’s responsibility to be vigilant—can decrease the likeliness that a medication error will occur and it’s also key in identifying systemic failures.^7,8

 

This Swiss cheese analogy can be applied to community pharmacy, where pharmacy staff establish multiple checkpoints during the filling process to ensure prescriptions are filled correctly (reviewing, scanning barcodes, tablet appearance, etc.). However, many patient safety cultures tend to look for explanatory causes for trouble and encourage blaming, criticizing, or silencing healthcare providers who make errors.⁴ For this reason, some experts refer to the individual who makes an error as the “second victim.” Lack of support from colleagues and supervisors can greatly affect involved health care providers’ ability to cope, leading to greater distress or protracted recovery.⁹

 

Fears of blame and punishment can deter individuals from reporting their errors, which can prevent creation of a culture of safety. Admitting one’s mistakes allows open discussion with peers and performance improvement experts can prevent further patient harm if they identify and fix the systemic “hole” causing the mistake.^2,4 Let’s look at systems-based approaches first, and then examine why individual approaches are also critical.

 

QUALITY AND PERFORMANCE IMPROVEMENT APPROACHES

Various workplaces take different approaches to errors, but risk managers have proven certain approaches are more successful than others (see Table 2). The two most common approaches to analyzing medication errors are tracking and trending. Almost every workplace, whether it’s a healthcare facility or some other kind of business—requires employees to complete incident reports if they make an error. A responsible individual (usually someone designated as a quality or performance improvement specialist or a risk manager, although individuals may be interested in looking at their own errors) should look at incident reports over time to determine

• What type of error or errors are most common
• If a particular drug or product is involved in multiple incidents and why
• The time of day or workload volume when the error occurred
• The individual or individuals involved

 

This amounts to a type of detective work, in which the responsible party investigates medication errors individually and collectively to track and trend predisposing factors. If the data indicates that certain factors are trending (occurring more than once), the workplace can take action to prevent the error from happening again.¹⁰ Sometimes the action is as simple as heightening employees’ awareness that errors have occurred. Other times, the workplace might place a sign on a shelf indicating that a product is a look-alike or sound-alike product, mark bottles with bright colors to differentiate them, use TALL man lettering (see SIDEBAR), or conduct training so staff is better educated.

 

SIDEBAR; What is TALL man Lettering?

TALL man lettering is the practice of writing part of a drug's name in upper case letters to help distinguish sound-alike, look-alike drugs from one another. The goal is to differentiate drug names visually and avoid medication errors. The Office of Generic Drugs of the U.S. Food and Drug Administration (FDA) encourages manufacturers to use TALL man lettering labels. Many hospitals, clinics, and health care systems use TALL man lettering in their computerized order entry, automated dispensing machines, medication admission records, prescription labels, and drug product labels. Does your system use TALL man lettering? If not, should it?

 

The Institute for Safe Medication Practices creates a list of TALL man lettering for drug names. Most—but not all—of the drugs on the list are generic products. Find the list here: https://www.ismp.org/recommendations/tall-man-letters-list.

 

Here’s a snapshot from the center of the list:

 

Drug Name with TALL Man Letters	Confused with
hydrALAZINE	hydrOXYzine – HYDROmorphone
HYDROmorphone	hydrOXYzine – hydrALAZINE
hydrOXYzine	hydrALAZINE – HYDROmorphone
medroxyPROGESTERone	methylPREDNISolone – methylTESTOSTERone
methylPREDNISolone	medroxyPROGESTERone – methylTESTOSTERone
methylTESTOSTERone	medroxyPROGESTERone – methylPREDNISolone
mitoXANTRONE	Not specified
niCARdipine	NIFEdipine
NIFEdipine	niCARdipine
prednisoLONE	predniSONE
predniSONE	prednisoLONE
risperiDONE	rOPINIRole
rOPINIRole	risperiDONE

 

Source: Reference 11

Table 2. Common Approaches to Medication Error-Related Performance Improvement

Term	Definition
Tracking	·       The ability to assess performance; following the course or trail of someone or something, usually to find them or note their location. In pharmacy, this could include: Product identification and verification, detection of and response to suspicion of illegitimate products Record keeping located in pharmacies, distributers, and providers’ records Patient data sharing to assist with medication reconciliation Recording all variances on unusual incident reports
Trending	·       Monitoring the general direction in which something is developing or changing. In pharmacy, monitoring has led to expansion of the pharmacists’ role. Examples include vaccination administration, collaborative practice agreements in certain states, tobacco cessation programs, and point-of-care testing. ·       A method of estimating future costs of health services by reviewing past trends in cost and utilization of those services.
Root cause analysis	·       A full investigation of the causes of unexpected events followed by identification and implementation of appropriate and effective strategies to prevent similar occurrence in the future. ·       Asking “Why?” until it cannot be answered, often employing a “fishbone diagram” that looks at potential issues with materials, machines, methods, environment, measurements, and people. ·       It helps pharmacies take a process-driven, system-based approach to address errors.
Workplace re-engineering	·       Planned elimination, addition, or distribution of functions or duties in the workplace focused on innovative strategies to develop leaders, engage employees, and foster healthy workplace culture. ·       Is often influenced by excessive or insufficient labor, poor patient outcomes, or political or economic changes.
Disaster drill or mock code	·       An exercise or demonstration that tests the readiness and capacity of a hospital, a community, or other systems to respond to a possible public health emergency or other disaster.

Source: References 12, 13, 14, 15, 16, 19

 

In the event a serious error occurs, workplaces need to go beyond simple steps. One such step is to conduct a root cause analysis (RCA). RCA starts by reviewing what and how an event occurred, and expands the investigation to identify why it happened. Many organizations explain to their employees that RCA is the art of asking “Why” until no more questions beginning with “Why” are possible. Armed with that information, the RCA team can develop workable corrective measures that prevent future events of the type observed. RCA is not flawless, but it ensures that teams of people look at very serious errors and develop approaches that could prevent them in the future.²⁰

 

Finally, errors are more likely to occur when unusual, unexpected, or unanticipated situations arise. For this reason, many organizations run disaster drills and observe them closely. In this way, they can identify areas where their systems are weak and implement corrective measures.²¹

 

Successful Programs

To create the best possible error prevention program, organizations can look at what has been proven to work. It’s clear that behavior-based programs create better outcomes than technology or any other approach.⁴ A leading researcher in pharmacy error identified six elements common to the most effective behavior-based programs (See Figure 1).⁴

 

Efforts that address the system and the individual jointly and individually are prudent. Consider a systemic safety measure: the widespread use of technology that is “smart.” Relying on technology and assuming it never fails may make some individuals become complacent and less vigilant until it is too late.⁴ Examples in community pharmacy are automated inventory systems and bar-code scanners. A person who enters data into a system—this would be an employee in the inventory management section in most pharmacies or healthcare systems—has a slight chance of entering an incorrect drug name. If no one catches the error, the last chance to prevent an error rests with the pharmacist who verifies that the tablet matches the description in the system before it is dispensed to the patient. The final check—a step that cannot and must not be automated—is an individual responsibility. Taking the extra seconds to verify the drug (while remembering that sometimes technology fails) can save a patient’s life from what could have been a deadly mistake.⁴

 

Many psychosocial factors also influence work performance. Work-as-imagined (work that is anticipated and described in official policies and procedures compiled by administrators or policy makers) and work-as-done (the way that employees actually accomplish work) are often quite different.²² Factors associated with the process of filling prescriptions are shown in Table 3.

 

 

Table 3. Psychosocial Factors that Influence Work Performance

• Anxiety or depression
• Changing workload
• Competing tasks
• Determination to “get the job done” despite barriers
• Distraction or interruption
• Hurrying
• Insufficient decision support
• Insufficient staffing
• Knowledge gaps
• Lack of experience
• Lack of non-technical skills training (examples include communication, decision-making, reasoning, team work, time management)
• Machinery or hardware that is difficult to operate
• Perception that an error could lead to criminal charges
• Rapidly changing or evolving roles
• Use of “work-arounds” (shortcuts or approaches that differ from procedure) to overcome barriers
• Vague or incomplete policy or procedure

 

Source: References 6, 22, 23, 24

 

The physical environment (inadequate illumination, environmental distractions, and noise), interruptions in workflow, facility design, technology, poorly designed labels, interpersonal relationships (e.g., number of interfaces with people and the level of stress and conflict caused by those interactions), and workload can adversely affect accuracy. ^25,26,27

 

Many pharmacy employees associate high workload with increased error rates. They are often surprised to learn that low-workload conditions are more closely linked with errors than high-workload conditions. Consider a study conducted in 2000 that involved pharmacists, pharmacy technicians, and 21,672 prescriptions. Pharmacy employees made more process errors under low-workload conditions (11.2%) than under high-workload conditions (6.1%) and during periods when the workload trended downward in volume (at the start of a shift or after a break).^28,29 In general, pharmacists were more vulnerable to mistakes when processing fewer than 15 prescriptions per hour than when processing more than 25 prescriptions per hour. (Author aside: We include these numbers because the study reported them, not as a hard and fast rule. We acknowledge that everyone has unique working habits, and some people can feel burned out processing fewer prescriptions than others.) A little bit of task tension (from perceived workload) seemed to result in fewer errors while filling prescriptions. However, there may be limits to the increases in task tension that would provide desirable results—too much stress and tension can become a problem. Overall, low levels of objective workload and subjective task tension were associated with more errors.^26,30

 

Personal qualities can also play a role. Impulsivity, task frustration, fatigue, perceptual ability, concern for doing well, a lack of physical hardiness, and magnitude of personal effort expended can cause more errors to progress through the verification process unnoticed. Individuals should examine their task-related anxiety and overall job-related depression (a strong predictor of overall job stress often manifesting as constant complaining at work, impatience with coworkers, the need for “mental health days,” difficulty getting up on workdays, or physical illnesses) and address them if possible. Supervisors should examine employees’ task-related anxiety and overall job-related depression to help individuals cope; if not, anxiety and depression will affect job satisfaction and performance.^4,22

 

Workplace support is also an important factor and the study mentioned earlier also demonstrated its importance. Pharmacists who had supervisors who they perceived as helping them set task goals and gain appropriate autonomy made fewer errors. Pharmacists who had supervisors who were overly autocratic (meaning domineering or overly involved in supervision) experienced tension that interfered with dispensing prescriptions accurately. Pharmacists who believed the number of breaks they receive was adequate to meet their needs made fewer process errors. ²⁶ Later studies also confirm that poor leadership and insufficient support can adversely influence accuracy.²²

 

ERRORS: WHAT WE KNOW

 

Errors are inevitable, but we must be able to recognize when we are prone to making errors to be able to limit them. Everyone has periods of increased errors—for instance during dramatic shifts in workload. Entering the pharmacy during peak hours can be stressful and predispose some individuals more than others to make errors they wouldn’t usually make. When we are flustered, our sense of logic escapes us momentarily.^4,26

 

Some individuals make more frequent or predictable errors than others because of different cognitive styles. A classic study found that pharmacists whose cognitive styles include attention to details made fewer errors. It also found that about 12% of pharmacists have difficulty attending to details, and that 12% of pharmacists made 33% of errors.²⁶ By using high-intensity task lights, exaggerated product label names (labels that are large and multicolored), NDC numbers, and specially designed devices for holding prescriptions at eye level during data entry, pharmacy staff who had difficulty being attentive to details made fewer errors.²⁶ An 1999 incident monitoring study found poor communication and failure to check medical records when questions arose also contributed to errors.³¹ A more recent PRIORITIZE study conducted between September 2013 and November 2014 involving 500 North West London primary care clinicians noted the top three problems relating to medication errors in primary care were incomplete medication reconciliation during transitions of care, inadequate patient education about medication use, and poor discharge instructions.³² Clearly, healthcare providers have some communication problems.

 

A patient case in Pennsylvania illustrates the alarming consequences of poor communication between healthcare providers and fewer medication reconciliations. The patient was first hospitalized for uncontrolled blood pressure and acute kidney injury. At the time of discharge, one of her prescription medications was Norvasc® (a high blood pressure medication). The patient experienced worsening fatigue, slow movements, personality changes, and a ‘stoic’ facial expression with suboptimal blood pressure control. Soon after, she was hospitalized the second time for chest pain and underwent angioplasty. Several weeks later, she was diagnosed with anxiety and depression and was prescribed prescription medications for these conditions. The patient was admitted a third time to the emergency room after a fall with light-headedness and poor ambulation. It was only at the third visit when the medication reconciliation team realized her outpatient pharmacy accidentally dispensed Navane® (generic name as thiothixene, an antipsychotic) instead of Norvasc®. When thiothixene was discontinued, her clinical status improved. This preventable medication error occurred because the pharmacy staff and physician deemed the written prescription legible, when in actuality, it was not.⁸

 

Typically, people make mistakes or slips most frequently when new to the profession and lacking experience. A long period during which mistakes are rare follows. Eventually everyone develops unique work habits, and error rates tend to increase again, usually as bad habits develop.^29,33

 

Finally, humans work on autopilot around 80% of the time. This means that 80% of the time, we don’t fully register what we are doing in our brain; we don’t engage with the task at hand and instead just go through the motions. Pharmacists also have an “inner pharmacist” who should kick in and take them out of autopilot mode when issues out of the ordinary arise.^30,34,35 Often, when faced with errors after-the-fact, we clearly recall the circumstances under which they occurred because we wake up from our autopilot. We’ll talk more about autopiloting below.

 

How People Work

Workload in the pharmacy has been traditionally measured as the number of prescriptions dispensed per hour or day, or the number of prescriptions dispensed per pharmacist. Experts predict that the typical pharmacist’s workload has and will increase for two reasons:

• An increase in demand from an aging population and
• The addition of pharmacist-provided services (examples include medication therapy management, helping women select oral contraceptives in some states, and immunizations).

 

Instead of only focusing on the numbers, pharmacists, pharmacy technicians, and the organizations that employ them should focus on understanding the individual’s subjective experience of work demands. For pharmacists, verifying patient’s information, performing patient consultation and drug utilization reviews, and verifying prescriptions for accuracy can be demanding to the point that high workload negatively impacts performance. For technicians, similar factors—performing repetitive and mundane tasks, expanding roles, and high-risk assignments—may increase stress or create situations in which they must multi-task. Understanding that work is a process and not a series of discrete events can help maintain the “big picture.”³⁰ That big picture is that pharmacists and pharmacy technicians must promote patient safety; dispensing to keep up with the pharmacy queue—the people who are in line or who have called in—is not prudent.³⁶

 

Over the course of the day, filling many prescriptions is bound to cause a person go on autopilot—which is understandable. Humans are creatures of habit and routine. All humans work on autopilot around 80% of the time.^4,34,35 Autopiloting occurs when the brain recognizes a situation and rapidly selects appropriate responses using familiar, predictable behavior context. The brain does this to preserve energy. Essentially, we perform most tasks reasonably well without thinking much about them. Many readers will sigh with recognition when they read this example: many people have left home on a non-work day to go someplace that’s in the general direction of work. They may be surprised to find themselves in their workplace’s parking lot. That’s autopilot. In the retail setting, pharmacy technicians and pharmacists autopilot the most when they are dealing with insurance coding and billing to third-party insurers. Autopiloting is usually safe.³⁷

 

Our autopiloting should stop when we encounter stressful situations that are unfamiliar because our brains don’t know how to react appropriately in unfamiliar situations. In stressful situations, we tend to misapply familiar rules and knowledge. Intense emotion blocks out our sense of logic. In these situations, we have to remember to exercise mindfulness—taking a little bit of time away from the regular work stream to assess the situation calmly and proceed with a plan of action.⁴

 

It’s also crucial for each worker to know his or her own tendency to make errors and do what is necessary to refocus.⁴ However, all pharmacy employees must recognize that some people’s propensities and capabilities are hardwired.³³ They cannot change their abilities and will approach work the same compulsive way, regardless of training.

 

Using technology to help us work is effective, but technology has limitations.³⁸ Technology makes us lazy and unfamiliar with manual processes that have been automated. It is common for individuals to become complacent because we believe a machine designed for a specific purpose will complete the task correctly for us. We tend to trust that technology will work well all the time. It doesn’t.³⁹ For instance, refilling a carousel cassette with the wrong medication will not prevent the machine from filling the prescription. This error can go undetected unless the pharmacist performs a final check before dispensing to the patient. This emphasizes the importance of the pharmacist’s individual responsibility as mentioned earlier.^4,39

 

Self-improvement

While all of us prefer not to make errors, expecting an error rate of zero is unreasonable.⁴ Errors will happen. As noted above, some people make more errors than others, and a landmark study found that 12% of pharmacists made 30% of reported errors.²⁶ Certainly, we all work with others who seem to make a disproportionate share of the workplace’s errors, and those who seem to be remarkably accurate. Where do you fall on the spectrum?

 

Examining your own error rate requires insight. This term—insight—is used most often in psychiatry and is defined as the patient’s awareness and understanding of the origins and meaning of his or her attitudes, feelings, and behavior, and disturbing symptoms.⁴⁰ It means understanding of oneself. It has a slightly different meaning in the context of medication errors. In problem solving, it means the sudden perception of the appropriate relationships between things that results in a solution.^41,42

 

Some people, and especially those who are error-prone, have poor insight. It may result from fixation, over-reliance on experience and past circumstances, rushing to solve a problem, or using the same approach over and over and expecting different results. Let’s look at each of these individually.

 

Fixation error refers to the tendency for the brain’s perceptual field to narrow and shorten in a crisis.^43,44 When this happens, we develop a sometimes stymieing compulsion to fixate on the problem we think we can solve, and ignore almost everything else. During periods of fixation, time becomes distorted; minutes often seem longer than usual. In addition, the fixated individual may not hear input from others. Even the most skilled and experienced professionals can develop a fixation in periods of high stress.^43,44

 

An example is that of a stalled car stuck on a level crossing as a distant train barrels toward it. The driver starts and restarts the engine, when the best way to save his life is to exit the car and run. In pharmacy, fixation errors occur when the provider concentrates on a single aspect of a case or problem to the detriment of other more relevant aspects. To break out of a fixation, individuals must be able to recognize the demand for a new approach to the problem and to produce a solution that works. Individuals who tend to fixate need to learn to^43,44

• Ask themselves what is different about the current problem
• Heighten awareness of the people around them and listen
• Invite others into the problem solving team to identify alternatives

 

Over-reliance on experience and past circumstances often occurs during emergencies. In this case, the individual tends to rely on past experience (even if it doesn’t apply in the current situation), and have difficulty abandoning assumptions based on that experience. In short, the person applies incident-specific experience to a situation that is probably much broader in nature. An example would be investigating why a patient who has asthma is experiencing exacerbations. If the pharmacist assumes the problem is treatment nonadherence when the actual problem is that the inhaler is faulty or requires skills like visual acuity or manual dexterity that the patient does not possess, the assumption can be deadly. In addition, during emergencies, individuals may have trouble recalling information accurately (elevated cortisol levels tend to change cognition and thinking). Often, using a cognitive aid like a checklist, decision tree, or an algorithm can help clarify thinking and lead to faster—and better—solutions.⁴⁵

 

It’s interesting that many pharmacy staff members say, “I was rushing,” when they analyze errors, but few studies looked at or identified rushing as a cause. Rushing to problem-solve can increase the likelihood of error. An older study found that physicians linked 10% of errors to rushing or fatigue.³¹ Experts in medication error science also indicate that rushing contributes to error.⁴⁶ An older study in Canada looked at a pilot program that transferred order entry responsibilities from pharmacists to pharmacy technicians. At the end of the study, the error rate had increased from 2.5% to 6%. Analysis indicated that technicians were rushing to enter orders, and re-training technicians to slow down and be mindful reduced the error rate to below the baseline level.⁴⁷ Often, technicians may try to fill more quickly, or pharmacists rush the final verification step of dispensing as the customer line lengthens, and errors occur.

 

One area of growing interest is interruptions and interruption management.^48,49 Interruptions have been shown to increase the medication error rate, and some studies suggest a technique called interruption management. They suggest using a “do not interrupt” sign or even a piece of clothing that warns people to stay away until the healthcare professional completes the task. They also recommend using a checklist for multistep processes. At this time, it’s unclear if these interventions help.^48,49

 

Finally, many of us have fallen victim to a common dilemma: using the same approach over and over and expecting different results.⁴ Healthcare practitioners as a rule, do many tasks—even complicated ones—from memory rather than from following a checklist. Over time, and especially when we see our error rates beginning to climb upward, it’s important to look at our own work and consider ways in which we need to adjust or change (see Table 4). We cannot rely on what we did before. Over time, people change, workplaces change, and many of the problem’s underlying elements change.⁴ As we analyze errors, we must include what we’ve learned in the past, but be open to fresh approaches and ideas.

 

Table 4. Improving Your Own Accuracy

Do this….	And then do this…
Periodically review your errors and near-misses.	Analyze errors to determine if you see a trend like confusing look-alike, sound-alike or spell-alike drugs. Determine if you can take steps to reduce the likelihood of a similar error happening again. Develop and use checklists if errors occur in multi-step processes.
Schedule visual and hearing exams more frequently as you age.	Wear appropriate glasses or hearing aids at work. Ask your employer for assistive devices (supplemental lighting, a magnifier, or a phone amplifier), or secure these yourself.
Solicit feedback from peers and supervisors about ways to reduce your own and others’ errors.	Maintain a quiet, composed demeanor in the workplace.
Address workplace distractions as soon as you become aware of them.	Reduce noise and clutter, improve lighting.
Understand technology’s limitations.	Maintain your skills so that if technology fails, you can revert to the pre-technology work method.
Value relationships with coworkers and promote good organizational dynamics.	Resolve disputes immediately, and retire grudges. Provide feedback to coworkers constructively.
Address developing personal problems (alcohol abuse, marital discord) early.	Engage with your employer’s employee assistance program before your supervisor refers you.
Understand that some people make errors because they lack knowledge.	Address your own knowledge gaps, and promote a culture of learning.
Avoid relying on “workplace re-engineering” or “work task design” to prevent errors; these may fail as the workplace composition and focus changes.	Learn to engage and listen to your “inner pharmacist” or “inner technician” when something is out of the ordinary.

 

When we discuss medication errors, it’s critical to talk about data entry errors because they represent about 25% of all medication errors.²⁵ The pharmacy has many repetitive tasks like data entry or filling prescriptions. Many of these tasks can be completed without conscious awareness. This ‘autopilot’ function contributes to data entry errors like misspellings or errors recorded on the patient’s profile. The vast majority of data entry errors are inconsequential, but some are dangerous.²⁵

 

Many factors could impact the cognitive system directly. Pharmacists and pharmacy technicians can take some simple steps to increase accuracy in the pharmacy. Figure 2 suggests a few, but individuals will find the best solutions are those they develop themselves and tailor to their own habits and circumstances.

 

 

Reducing Workplace Turbulence

Workplace turbulence occurs when something causes discomfort or decreases workplace stability. Some things that cause workplace turbulence include poor temperature control (it’s either too hot or too cold), noise, clutter, uncertainty, or working with people who have different styles or personalities that are abrasive to you. These things affect accuracy and productivity. If workplace distractions are the problem, making small changes to decrease turbulence can make large differences.^29,33

 

If the problems are environmental, ask the appropriate person to help resolve them. Establishing good relationships with the people who provide environmental support—people in building supervision, maintenance, and housekeeping—is imperative. They can often help adjust the ambient temperature or reduce clutter. Learning to work with instead of against or parallel to coworkers and supervisors can improve the environment.⁴ The key is telling your supervisor how you best hear constructive criticism and delivering constructive criticism to others in a positive way—and in the way they receive it best.

 

Finally, be aware of when you are fatigued or unable to perform at your peak and enlist coworkers' help by asking them to monitor your work.^29,33

 

Poka-Yoke

Since the 1960s, many industries have adopted the principles of poka-yoke, also called “mistake-proofing,” to prevent errors.⁵⁰ Poka-yoke is a systems approach, but unlike many systems approaches, the people closest to the work (not administrators or policy makers) propose the action. Defined broadly, poka-yoke refers to any behavior-shaping constraint in a process that prevents faulty behaviors by the worker. An industrial engineer at Toyota developed this concept, and it encourages workplaces to look at common mistakes and develop processes that make it impossible for workers to make the mistake in the future. Basically, it’s defensive workplace design. It depends on involving the people closest to the work to identify what to mistake-proof and develop ideas to prevent very specific mistakes. In pharmacies, four poka-yoke principles are used often, and can be applied in many more areas.^50-52

 

First, workplace managers need to empower employees to pause or even stop the work process entirely if they believe that an error is in process.²⁹ Employees need to be able to ask four questions respectfully:

• Did we do everything?
• Did we do everything right?
• Does it look, sound and feel right?
• Are these our usual work conditions?

 

Next, everyone in the pharmacy community from manufacturers to distributors to providers who work in direct patient care need to make it easier for people to do the right thing than the wrong thing. A short example can clarify this principle. Years ago at the National Cancer Institute, a collaborating company was developing a new monoclonal antibody (MAB). The MAB was lyophilized and came in a fairly large multidose vial. It needed to be reconstituted with 20 mL of a specific diluent. The manufacturer provided the MAB with a vial of the diluent that contained 30 mL. The astute reader will see the potential for error. In many cases, pharmacists and pharmacy technicians who worked in investigational drug preparation looked at the package, and simply transferred the diluent—all 30 mL of it—into the larger vial. The resultant solution was an incorrect dose. Can you see why? Diluting a 400 mg vial with 20 mL creates a 20 mg/mL solution. Using 30 mL creates a 13.33 mg/mL solution. After investigational drug employees identified and reported this error several times, and the NCI reported it to the manufacturer, the simple poka-yoke fix was implemented. Although it took quite some time to implement the change, eventually the manufacturer packaged the MAB with a vial of diluent that had the correct amount needed in it—20 mL.

 

People who work in pharmacy in any capacity can make it easier to do the right thing than the wrong thing in numerous ways. Let’s discuss four of them.

• Putting items that will always be used together in that same container, and making sure that the items that are assembled are the correct sizes or doses or quantities, is kitting at work. It results in fewer missing parts, and it also speeds your process. Some experts estimate that it can cut errors by as much as 80%.⁵³ The solution noted above is an example of kitting. Other examples of kitting are creating bowel evacuation kits for patients having colonoscopies, or assembling packages of items that are frequently prescribed together for specific procedures or treatments.
• Keying simply means that a process can’t be started without a key or tool of some sort. The requirement to remove your ATM card before receiving cash is an application of this principle so people don’t leave their cards in the machine. An example in the pharmacy is a computer that requires the user to insert an ID card to start the system. This increases accuracy and prevents users from signing in early in the day, walking away from the computer, and allowing others to operate under an incorrect sign-in code. Another example of a type of keying is moving pseudoephedrine to behind the counter in the pharmacy. Adding that step—requiring customers to sign for pseudoephedrine and limiting quantities—ensures there is a check in the process. States that have implemented this step have decreased the amount of pseudoephedrine diverted to methamphetamine production significantly.
• Interlocking uses simple mechanisms so that parts will only fit with other appropriate pieces. These are simple, low cost devices that prevent parts from being assembled incorrectly. An everyday example of poka-yoke for someone who always forgets or loses his keys is to place the keys in the shoes he will wear tomorrow. An example in pharmacy might be providing drugs meant to be administered intrathecally in a device that cannot attach to any intravenous equipment.
• Tell-tales let you know when you have made an error. Barcoding is a type of telltale. When you scan a barcode and it doesn’t match the barcode on the actual order, it sends you an alert that you’ve made an error.

 

The last poke yoke principle we’ll cover is this: Make mistakes obvious to workers immediately and discretely so they can make on-the-spot corrections, and allow people to take corrective actions or stop the work flow before irreversible damage is done. This small kindness brings errors to the error-maker’s attention, and allows immediate learning.

 

CONCLUSION

Despite our best intentions, some errors escape the confines of the pharmacy. Randomly checking completed work that has apparently passed verification sometimes identifies problem areas. But, some errors are just that—unfortunate events that could not be anticipated and occurred due to a confluence of factors. Even though reaching a medication error rate of zero is improbable, we should still make efforts to acknowledge our professional responsibility in our own work habits. Creating solutions tailored to our habits and circumstances can help reduce error rates and encourage a focus on a workplace culture of patient safety—not the number of prescriptions filled—as the big picture in pharmacy.

 

 

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