Azithromycin & levofloxacin safety concerns continue

- Jennifer Middleton, MD, MPH

Safety concerns with azithromycin and levofloxacin seem to be mounting of late, and a new study titled "Azithromycin and Levofloxacin Use and Increased Risk of Cardiac Arrhythmia and Death," just published in the Annals of Family Medicine, adds fuel to the fire.

Rao et al conducted a retrospective cohort study, comparing US veterans who had received azithromycin or levofloxacin to those who had received amoxicillin. The researchers looked at outcomes during the 10 days after starting one of these three antibiotics (first dose of antibiotic = day 1). Participants were excluded if they had been on another antibiotic in the month prior to receiving one of the three antibiotics and/or if they had any current "life-threatening" condition. The researchers then looked through participants' charts and identified which ones had been admitted for a serious cardiac arrythmia (long QT syndrome, ventricular tachycardia, ventricular fibrillation, ventricular flutter, or cardiac arrest), been evaluated in the emergency department with one of those cardiac arrythmias, and/or had died of any cause.

They found that, compared to amoxicillin, treatment with azithromycin and levofloxacin was associated with an increased risk of both death and serious cardiac arrythmia.

During days 1-5, the hazard ratio (HR) for risk of death with azithromycin was 1.48 (95% Confidence Interval 1.05-2.09) and the HR for risk of death with levofloxacin was 2.49 (95% CI 1.70-3.64). In days 6-10, the HR for death in the azithromycin group was no longer statistically significant (1.14 95% CI [0.81-1.62]) but the HR for death in the levofloxacin group still was (1.95 95% CI [1.32-2.88]). The data for cardiac arrythmias follows a similar trend and may be viewed here.

The authors do note that a similarly styled study in Denmark last year was reassuring regarding these risks in a young, healthy cohort, but caring for older men with multiple co-morbidities is a significant portion of my patient panel and, I suspect, is for a significant number of other family docs as well. These men are more likely to have pneumonia, for which I frequently use one of these drugs, and azithromycin and levofloxacin are also recommended for patients with severe COPD exacerbations.

This study's findings warrant attention, even if it is a retrospective study. Although many physicians prefer basing practice change on a prospective study, retrospective studies are better suited than prospective studies to detect rare events. With a prospective study, researchers would need to identify large groups of participants and potentially follow them for a long time before having enough cases to meet statistical rigor. That can take a lot of expense and time to accomplish and can be an understandable turn-off for a potential researcher. So, this retrospective cohort study may be as good as it gets for a while.

As for me, I'll be checking out the AFP By Topics on Pneumonia and COPD to investigate alternative antibiotics to use in my older male patients. How about you - will this retrospective cohort study change how you prescribe azithromycin and/or levofloxacin?

Truth and consequences of antibiotic overuse

- Kenny Lin, MD, MPH

The cover article of AFP's March 15th issue, "Common Questions About Clostridium Difficile Infection," reviews truths about a disease that is a direct consequence of medicine's good intentions: antibiotic use, both appropriate and inappropriate. A recent Vital Signs report from the Centers for Disease Control and Prevention (CDC) addressed the magnitude of the latter by demonstrating that broad-spectrum antibiotics are up to three times as likely to be used in some hospitals compared to others. Additional analyses concluded that 37 percent of prescriptions for intravenous vancomycin and antibiotics for urinary tract infections were not supported by diagnostic testing or documentation of symptoms.

The CDC estimated that reducing the use of broad-spectrum antibiotics by 30 percent could eliminate more than 1 in 4 Clostridium difficile infections. CDC Director Thomas Frieden, MD, MPH outlines seven steps for hospitals to improve accountability and monitoring of antibiotic prescribing in the video below.



Increasingly, Clostridium difficile infections are occurring in outpatient as well as inpatient settings. A study published in Pediatrics revealed that 71% of laboratory-confirmed Clostridium difficile infections identified by a U.S. population-based surveillance system from 2010 to 2011 were community-acquired, with the highest incidence among children 3 years of age or younger.

According to the AFP review article by Dr. Bradford Winslow and colleagues, many Clostridium difficile infections can be prevented by minimizing the frequency and duration of antibiotic prescriptions; practicing hand hygiene and adhering to contact precautions; and prescribing probiotics to patients who are taking antibiotics for infections.

Weight loss medications: how much of a solution are they?

- Jennifer Middleton, MD, MPH

I have patients requesting prescriptions for a weight loss medication nearly every week, and I suspect that many family docs could report the same. Some of these patients would likely benefit from losing 10-20% (or more) of their body weight, and some just want to lose "that last 5 pounds." Some of these patients are already doing a great job with lifestyle modifications, and some want the ease of a pill that allows them to avoid exercise and/or nutrition changes. I rarely prescribe weight loss medications, as I have doubts about their long-term efficacy, and I worry about their side effects. I will only prescribe them to a patient who is already working on lifestyle changes and would likely benefit from a significant weight loss.

The current issue of AFP includes a POEM of a systematic review published in JAMA earlier this year regarding the benefit of prescription weight loss medications. This thoughtful systematic review only included studies of at least 1 year's duration and looked at lipid, glucose, and blood pressure outcomes in addition to weight lost.

The medications included in the review were orlistat, lorcaserin, and phentermine/topiramate. Interestingly, no studies examining phentermine alone met the systematic review's 12 month duration requirement, even though, as the POEM notes, it's the most commonly prescribed weight loss medication. The AFP POEM provides the average weight lost among all studies (2.5 - 8.0 kg), which is a useful adjunct to the wide range of "successful weight loss" (where "success" = at least 5% body weight lost) percentages quoted in the original study's abstract.

All of the studies measured the effect of these medications along with nutrition and exercise changes, so I feel justified in continuing to insist upon lifestyle changes prior to initiating treatment with any of these medications. The authors also recommend discontinuing weight-loss medications if 5% body weight is not lost in 12 weeks, as participants who did not lose at least that much weight were unlikely to lose any after continued medication.

The POEM points out that this systematic review did not, however, find any evidence of POEM (Patient Oriented Evidence that Matters) level benefit for these medications besides weight loss. Lipid, glucose, and blood pressure readings are all disease-oriented evidence (DOE); we have no studies to date showing that any of these medications reduce complications from hypertension, diabetes, heart disease - or even whether they help people live longer. It seems reasonable to assume that patients who lose weight with these medications will improve their risk of those complications, but that's only an unverified inference at this point.

The study's authors state that "[t]he need for constant vigilance to sustain behavior changes in the face of biologic and environmental pressures to regain weight emphasizes the challenges faced by even the most motivated patients who have achieved weight loss." They then use this statement to validate the importance of weight loss medications as a way to combat those pressures. Frankly, I'd prefer to see us work to lessen those biologic and environmental pressures instead of adding another pill to our patients' regimens. Our commitment as 21st century family physicians must be to our communities as well as our individual patients if we are ever to turn the tide of rising obesity rates. There's an AFP By Topic on obesity if you'd like to read more.

That said, here in the here and now, these medications may have a role to play. Are you prescribing medications to help your patients lose weight? If so, how do you choose which patients to prescribe them to?

Too much testosterone therapy?

- Kenny Lin, MD, MPH

If the ubiquitous television advertisements are to be believed, there is an epidemic of low testosterone (or “low T” for short) sweeping America. Men of all ages have been instructed in these advertisements to “ask their doctor” if they have any one of a list of nonspecific symptoms that could be improved with testosterone therapy. (Future AFP editorials will address the controversy about widespread testing for low testosterone levels.) Although hypogonadism is the only widely recognized indication for testosterone supplementation, recent research suggests that substantial numbers of men without testosterone deficiency are receiving prescriptions.

Concerns about excessive testosterone therapy led the Endocrine Society and the American Urological Association to recommend in the Choosing Wisely campaign that clinicians not prescribe it to men without biochemical evidence of testosterone deficiency, including men with erectile dysfunction and normal testosterone levels. In addition to having questionable benefits for these patients, supplementation is potentially harmful. Recent studies have linked testosterone therapy to an increased risk of cardiovascular events in men over age 65 and in younger men with heart disease.

The Endocrine Society recently recommended that physicians talk with patients about these potential risks and avoid prescribing testosterone to men without hypogonadism. In the meantime, the U.S. Food and Drug Administration is re-evaluating the risk of stroke, heart attack, and death associated with testosterone products. Given well-documented efforts of pharmaceutical companies to expand the market for testosterone therapy by ghostwriting articles for lay and scientific publications, family physicians would be wise to steer clear of commercially-sponsored educational offerings (disclosure of conflicts of interest is not enough) and restrict prescriptions of testosterone to patients with FDA-approved indications.