Monday, July 9, 2018

Minimizing adverse effects from antibiotics: short duration + narrow spectrum

- Jennifer Middleton, MD, MPH

Adverse effects are not uncommon with antibiotics, and two recent POEMs (Patient Oriented Evidence that Matters) in AFP review strategies to minimize them. The first POEM found that shorter courses of antibiotics are equivalent to longer courses for several common outpatient infections. The 2nd POEM found that, for outpatient respiratory tract infections in children, narrow-spectrum antibiotics have a lower risk of adverse effects compared to broad-spectrum antibiotics with equivalent treatment efficacy.

The first POEM is a systematic overview of 9 systematic reviews comparing antibiotic treatment durations for urinary tract infection (UTI), acute pyelonephritis, sinusitis, and community-acquired pneumonia (CAP) in adults, and strep pharyngitis, CAP, UTI, and acute otitis media (AOM) in children. They found that:

AOM (children): 7 or less days =  more than 7 days
CAP (children): 3 days = 5 days
CAP (adults): 7 or less days = more than 7 days
Strep pharyngitis (children): 5-7 days = 10 days
Sinusitis (adults): 3-7 days = 6-10 days
UTI (children): 2-4 days =  7-14 days
UTI (non-pregnant, premenopausal women): 3 days = 5 or more days
UTI (older women): 3-6 days = 7-14 days
The authors found a reduced risk of adverse events for patients treated with shorter durations for AOM, sinusitis, and younger women with UTI; they found no difference among patients with pharyngitis, pyelonephritis, or older women with UTI. Adverse event data was not available for patients treated for CAP or children with UTI.

The 2nd POEM included both a large retrospective cohort arm (over 30,000 children) that reviewed outcomes of children with sinusitis, AOM, or strep pharyngitis diagnoses and a prospective cohort arm (almost 2500 children) examining the same conditions. The findings of the retrospective arm and the prospective arm concurred: broad-spectrum antibiotics (amoxicillin/clavulantate, cephalosporins, macrolides) offered no treatment benefit over narrow-spectrum antibiotics (penicillin, amoxicillin) but did increase the rate of reported adverse effects. The retrospective cohort only reported adverse event rates as documented in the medical record, but the prospective cohort included data gathering of adverse events from parents. The prospective cohort had a much higher rate (10.3 times higher) of adverse effects reported by parents, suggesting that many patients and/or their parents are not reporting these events to physicians.

It's possible that some of the patients who received antibiotics in these studies did not need them at all, thus explaining the lack of benefit in longer antibiotic treatment durations; for example, most cases of acute bacterial sinusitis will resolve without antibiotics (consider offering an intranasal corticosteroid instead), and deferring antibiotics for AOM in children over the age of 2 years with non-severe symptoms is a Choosing Wisely recommendation. Determining which patient needs an antibiotic is not always clear, either; Centor scoring can assist with pharyngitis, but, as Dr. Lin reviewed last week on the blog, procalcitonin levels may not distinguish CAP from lower respiratory tract infections that don't improve with antibiotics (such as bronchitis).

Limiting antibiotic overuse benefits patients and communitiesAFP's Choosing Wisely tool facilitates quick review of these recommendations, and there are also AFP By Topics on Pneumonia, Respiratory Tract Infections, and Urinary Tract Infections/Dysuria that include resources on diagnosis and treatment. 

Tuesday, July 3, 2018

Does procalcitonin make it easier to choose antibiotics wisely for respiratory infections?

- Kenny Lin, MD, MPH

American Family Physician has supported the Choosing Wisely campaign in several ways since it began in 2012, from maintaining a searchable database of primary care-relevant recommendations, to including tables of best practices in clinical review articles, to publishing an occasional editorial containing suggestions of how to implement it into practice. Although Choosing Wisely remains very much a work in progress, staff at the American Board of Internal Medicine Foundation recently identified a "Top 12" list of recommendations that are successfully reducing overuse in health systems across the United States. Leading the list is appropriate use of antibiotics for patients with upper respiratory tract infections, a topic that has been previously reviewed in this journal.

A more challenging task for family physicians may be deciding which patients with lower respiratory tract infections need antibiotics - distinguishing acute bronchitis from chronic obstructive pulmonary disease exacerbations or community-acquired pneumonia. Although clinical decision tools exist, their usefulness in outpatient settings is limited. A Cochrane for Clinicians in the July 1 issue reviewed the benefits and harms of procalcitonin-guided antibiotic therapy compared with routine care for acute respiratory infections on mortality, treatment failure, duration of antibiotic exposure, and antibiotic-related adverse effects. In a meta-analysis of 26 randomized, controlled trials (n = 6708), patients receiving procalcitonin-guided therapy had lower 30-day all-cause mortality (NNT=71) across all settings, but no difference in primary care settings. Rates of treatment failure were similar. Total duration of antibiotic exposure was 2.4 days lower in the procalcitonin group, corresponding to a lower percentage of patients in the procalcitonin group experiencing antibiotic-related adverse effects (16.3% vs. 22.1% in the control group).

Should this evidence lead clinicians to adopt procalcitonin-guided therapy algorithms to improve antibiotic stewardship for acute respiratory infections? Limitations of the Cochrane review are worth noting: the studies were relatively small (mean 258 participants); most were in Europe rather than in the U.S.; and most were in emergency department rather than primary care settings. After the review's publication, Dr. D.T. Huang and colleagues reported the results of a large (n=1656) RCT in 14 U.S. hospitals that compared procalcitonin-guided antibiotic therapy with usual care for patients with lower respiratory tract infections in the emergency department and on the inpatient service, if applicable (782 patients were subsequently hospitalized). In contrast to the Cochrane review, the investigators found no significant differences between the groups in duration of antibiotic exposure or adverse outcomes. They concluded that the addition of procalcitonin results did not significantly improve antibiotic decision-making or patient outcomes.

A take-home message from the Cochrane review and the recent U.S. trial is that the effects of procalcitonin measurement on diagnosis and management of acute respiratory infections depend on the clinical setting, patient characteristics, and preexisting adherence of clinicians to high-value care guidelines for antibiotic prescribing. This test may be helpful in certain cases, but probably should not be used routinely.

Monday, June 25, 2018

Which prescription medications are linked to depression?

- Jennifer Middleton, MD, MPH

Perhaps your patients have asked you if the medications they're taking are linked to an increased risk of depression as this study, "Prevalence of Prescription Medications with Depression as a Possible Adverse Effect Among Adults in the United States (US)," has been widely disseminated in the lay press over the last week.

The authors examined data from 2005-2014 from the National Health and Nutrition Examination Survey (NHANES), which included over 26,000 US adults. The NHANES data includes all medications that participants reported during these times, and the study authors identified medications that have depression as a listed potential side effect, which they termed "depression adverse effect medications." Overall, during this 10-year time period, 21% of surveyed adults took at least 1 of these medications, 8.7% took 2, and 7.5% took 3 or more. The prevalence of depression increased proportionally to the number of depression adverse effect medications adults were taking; adults taking none had a 4.7% prevalence of depression, adults taking 1 had a 6.9% prevalence of depression, adults taking 2 had a 9.5% prevalence of depression, and adults taking 3 or more had a 15.3% prevalence of depression. The most commonly prescribed depression adverse effect medications were metoprolol, atenolol, omeprazole, hydrocodone, gabapentin, and oral contraceptives. Use of multiple non-depression adverse effect medications was not associated with an increased prevalence of depression.

Observational studies can only prove correlation, not causation; the authors appropriately limited their conclusions to noting linkages between depression diagnoses and the use of depression adverse effect medications. The premise that we should consider how the medications we prescribe might contribute to mood diagnoses, however, is a reasonable one. The authors note that current screening instruments do not include review for possible depression adverse effect medications; it may be worth considering adding an assessment of current medications to whichever tool your practice uses.

The United States Preventive Services Task Force (USPSTF) recommends screening all adults for depression, and there is still plenty of room to improve mental health screening rates in the US. There's an AFP By Topic on Depression and Bipolar Disorder that includes this article on "Screening for Depression" that describes currently available instruments.

Will these results from the NHANES change how you prescribe medications that may contribute to depression?

Monday, June 18, 2018

Safe summer travel tips for you and your patients

- Kenny Lin, MD, MPH

As children finish school and the summer vacation season gets underway, readers of American Family Physician should know about all of the resources available in our archives for prevention and management of medical conditions in travelers, the best of which are included in our Travel Medicine collection. Family physicians can brush up on key components of the pretravel consultation for international travelers, including vaccination updates and malaria prophylaxis. Patients who plan to play in the water can be provided with recommendations for preventing recreational waterborne illnesses and tips for avoiding neurologic complications of scuba diving or surfing-related injuries.

Depending on the vacation destination, clinicians may need to counsel patients on risk factors and symptoms of altitude illness (which includes acute mountain sickness and less commonly, cerebral and pulmonary edema) or emerging vector-borne diseases such as West Nile virus, Dengue, Chikungunya, and, of course, Zika virus. A 2015 editorial reviewed advice for protection against mosquitoes and ticks that carry these and other diseases (such as Lyme disease, which doesn't always present with a classic "bull's eye" rash).

And whether your own summer plans include going on a medical humanitarian mission or just relaxing at your favorite fishing hole, AFP has you covered. Clinicians who plan to spend time near any body of water - including the backyard swimming pool - should consider familiarizing themselves with the essentials of prevention and treatment of drowning.

You can access patient education handouts on all of these activities and more from AFP and FamilyDoctor.org in your office and on the go.

Monday, June 11, 2018

Vitamin and mineral supplements don't improve mortality

- Jennifer Middleton, MD, MPH

A recent systematic review of "Supplemental Vitamins and Minerals for CVD Prevention and Treatment" has been making the rounds in the lay press for the last week; perhaps your patients have mentioned it to you as several of mine have. Sales of vitamin and mineral supplements have only increased since 2010 in the United States, with an estimated 36 billion dollars spent by consumers on these products in 2017. Perhaps this new systematic review will convince at least some of our patients to save their money, as most supplements were not found to improve CVD outcomes, and none improved overall mortality.

The authors included 179 randomized controlled trials in their final analysis; no vitamin or mineral supplement improved overall mortality. Folic acid use did correlate with decreased cardiovascular disease (CVD) risk, and folic acid and B-vitamin supplementation correlated with decreased stroke risk; the number needed to treat (NNT) for folic acid to prevent 1 CVD event was 167, the NNT for folic acid to prevent 1 stroke was 111, and the NNT for B-vitamin complex vitamins to prevent 1 stroke was 250. Use of multivitamins, vitamin C, vitamin D, beta-carotene, calcium, and selenium did not correlate with any change in mortality. Unfortunately, antioxidant products and niacin (when taken with a statin) did correlate with an increase in total mortality; the number needed to harm (NNH) for antioxidant supplements to cause 1 death was 250, and the NNH for slow-release niacin when taken with a statin was 200.

Dr. Lin wrote earlier this year for the blog, and in print for AFP, that vitamin D screening and supplementation is an ineffective use for finite healthcare dollars. Calcium supplements have not been found to improve outcomes related to osteoporosis, but they have been linked to an increase in CVD deaths. The Choosing Wisely campaign advocates against taking a "multivitamin, vitamin E, or beta-carotene to prevent cardiovascular disease or cancer."

Certainly, in specific situations, some vitamin and mineral supplements are useful. Iron and vitamin B12 deficiencies, when identified, are reasonable to treat. Calcium supplementation may improve premenstrual syndrome symptoms. Vitamin B6 is a safe and effective treatment for nausea and vomiting in pregnancy. In each of these scenarios, however, supplementation is only useful once a clinical problem has been identified. The systematic review mentioned above reinforces that empiric vitamin and/or mineral supplementation is unlikely to be beneficial for our patients - and may even be harmful.

Vitamin and mineral supplements can't take the place of consuming a healthy, nutrient-rich diet, and the United States Preventive Task Force (USPSTF) even has a B recommendation regarding the benefit of such counseling "to promote a healthful diet." There's an AFP By Topic on Nutrition if you'd like to read more, which includes several useful patient information resources.

Wednesday, May 30, 2018

Guest Post: Practicing what I preach about generic drugs

- Kathleen "Cook" Uhl, MD

In 2015, I was treated for stage 3 colorectal cancer. All of my cancer medications – from the chemotherapy right down to the anti-nausea medications – were generics.

Why did I take only generic medicines? Through my work at the U.S. Food and Drug Administration (FDA), I know that FDA-approved generic drugs meet the Agency’s high standards for safety, efficacy, and quality. So when my doctors at Walter Reed National Military Medical Center prescribed me generic cancer medications, I was confident that the generic prescriptions were as high-quality as brand-name medications, and could be substituted for the brand-name drug with no difference in safety or efficacy.

The generic drug approval process is supported by solid scientific research and review. Generic drug manufacturers must demonstrate their product is pharmaceutically equivalent and bioequivalent to the brand-name product before it can be approved. They also must demonstrate that the generic drug can be reliably and consistently manufactured in a way that maintains this equivalence and quality.

Pharmaceutical equivalence means that the generic has the same active ingredient, strength, dosage form, and route of administration as the brand-name drug. Formulations may differ in inactive ingredients, provided that the generic drug manufacturer shows the inactive ingredients are safe and do not change the way the active ingredients are delivered to the body. Generic drugs may also have differences in characteristics such as size, shape, or color.

FDA standards of bioequivalence often require companies to conduct in vivo bioequivalence studies. Typically, volunteers take the brand-name and generic drug products to demonstrate that there is no significant difference between the rate and extent of absorption of the active ingredient. A bioequivalent drug will behave the same way in patients as its brand-name counterpart. FDA scientists compare data from these studies to ensure that a generic drug can be substituted for its brand-name counterpart and will behave the same way in patients.

Makers of generic drugs also submit data to FDA to show how the processes of combining the active and inactive ingredients to make the generic drug meet the same standards as the brand-name drug. It is only when a generic drug manufacturer has demonstrated that it can reliably make a high-quality, pharmaceutically equivalent and bioequivalent product that it can be made available to patients.

I am a cancer survivor. I am alive today because of the love and support of my family, friends, and co-workers. I am alive because of the incredible doctors and medical staff at Walter Reed. I am also alive because of generic drugs. Generic drugs saved my life.

**

Dr. Kathleen "Cook" Uhl is Director of the Office of Generic Drugs in the Center for Drug Evaluation and Research at the U.S. Food and Drug Administration. Her editorial "How the FDA Ensures High-Quality Generic Drugs" appeared in the June 1 issue of AFP.