Chances are, across this great land of ours, right at this very moment, someone is coughing, or sneezing, or struggling with a sore throat, or some combination of the above, and taking the antibiotic azithromycin. Or they might be just fevering, with no discernible cause, and still they’re taking azithromycin.
They might have obtained it from an urgent care clinician, an online telehealth service, a supply they had stashed away “just in case,” or any number of sources that most likely didn’t assess whether the benefit of taking the antibiotic outweighed the risk.
Here’s the thing — there’s a very high likelihood it’s doing them no good at all, and there are a bunch of reasons why it might actually be harmful. As an example, more than a decade ago, I wrote about data linking azithromycin to increased cardiovascular events.
Before we get to this and other problems with azithromycin (Part 2 — it’s coming!), let’s take a look back at the history of this extremely popular antibiotic and how it achieved its pre-eminent position in outpatient medicine.
Erythromycin: An Antibiotic That Packed a Punch (to the Gut)
Back during the Ronald Reagan years, the macrolide antibiotic erythromycin was the leading alternative to penicillin. Widely used in people with penicillin allergies — real or otherwise — erythromycin nonetheless had several disadvantages, the most important of which was an incredibly high rate of gastrointestinal side effects.
Nausea. Abdominal cramping. Diarrhea. Bleh.
Typical doses were 250 mg four times a day, or 333 mg three times daily, often prescribed for a week or even longer. The thrice-daily 333 mg dose was more convenient, and supposedly better tolerated, but frankly sparing that 1 mg/day didn’t do much to reduce its side effects.
True story — my first attending physician in a medical school hospital rotation was a gastroenterologist. He’d come down with the sniffles, and he told us he started himself on erythromycin “just in case” (second time I’m using that phrase).
A couple of days later, he didn’t look so great — all pale and sweaty. Trying to be compassionate, I asked how he was feeling. His response: “The cold is better but the nausea from the erythromycin is a killer.”
Oh Physician, heal thyself! Erythromycin doesn’t treat colds!
(I did not tell him that. I was a third-year medical student.)
The New Kids on the Block: Clarithromycin and Azithromycin
Then, in 1991, with much fanfare, two new macrolides appeared on the scene — clarithromycin and azithromycin. Both promised to improve on erythromycin by treating a broader range of pathogens and, most importantly, having fewer side effects.
Hooray for both! Advertisements for Biaxin (clarithromycin) and Zithromax (azithromycin) bombarded doctors in medical journals. Paging through the latest issue of The New England Journal of Medicine or The Lancet, we might come across something like this:
Source: Center for the Study of Tobacco and Society
Drug advertising back then was a huge source of revenue for medical journals — remember, this was before the internet. The makers of Biaxin and Zithromax were not shy about their new and improved versions of erythromycin, which really were objectively better in many ways.
We don’t hear much about clarithromycin anymore, and for good reason. Glossy ads notwithstanding, clarithromycin never quite delivered on its promise. It also caused GI side effects (though fewer than erythromycin), had major drug interactions, prolonged the QT interval, in some studies increased mortality — and could make food and drink taste absolutely bizarre.
The medical term for taste disturbance is dysgeusia, by the way — pronounced dis-GYOO-zee-uh, which kind of sounds like what it means. You’ll win big points among your friends if you casually drop this word into everyday conversation.
Another true story: A colleague of mine from a prestigious academic medical center in Baltimore boarded a flight to Europe and was upgraded to first class. Handed the complimentary glass of champagne, he tasted it and nearly spat it out. He insisted to the flight attendant that it was flawed and asked for a glass from a different bottle — which, to his disappointment, tasted the same.
Only later did he realize that the clarithromycin he was taking for sinusitis made everything taste like he was drinking from a rusty metal pipe.
So the real champ in the Battle of the New Macrolides was azithromycin, which had a few tricks up its sleeve that made it irresistible to clinicians and patients alike:
- It had fewer side effects than clarithromycin. None of that dysgeusia weirdness. (It’s fun to write, and to say, dysgeusia. I’ll stop doing so now, promise.)
- It had fewer drug interactions.
- It didn’t affect cardiac conduction quite as much, an important safety feature.
- Most importantly, it stuck around in the body for a very long time. The half-life of azithromycin is a stellar 68 hours (nearly 3 days)!
Pharmacologists oohed and aahed over this aspect of azithromycin, which was made even more impressive by its high concentrations within cells and tissues — where it lasted even longer than in the blood.
Enter the Z-Pak. Read on!
Z-Pak Reigns Supreme: The Rise of Azithromycin
What truly transformed azithromycin from a useful antibiotic into a cultural phenomenon was the way its pharmacology was leveraged into the first truly “short-course”
antibiotic.
Instead of the traditional antibiotic regimen (three or four pills a day for 7 to 10 days, ideally taken with food but not dairy, dispensed in an orange plastic bottle with a white cap), azithromycin came as six pre-packaged pills.
Generated by AI but trust me — it looked like this!
Here were the directions:
- Day 1: Two tablets (500 mg total) once
- Days 2 through 5: One tablet (250 mg) daily
Just six pills. Just 5 days. The Z-Pak is born!
The now-iconic Z-Pak took a concept from a pharmacokinetics lecture and turned it into something instantly graspable for clinicians and patients alike. A tidy blister pack. Clear instructions. A sense of completion. You finished it, decisively, in less than a week. For busy clinicians and busy patients, it felt like modern medicine at its best.
Marketing, of course, played a major role, most notably when the approval was broadened to include children, who got away with taking just 3 days. This is the United States of Advertising, after all! We’d expect nothing less.
At pediatric hospitals and in outpatient clinics, replicas of Max the Zebra — the drug’s mascot, “ZithroMAX”, get it? — dangled from stethoscopes. Medical journals arrived wrapped in zebra-striped covers. Branded stuffed animals appeared in exam rooms to comfort anxious children. In one particularly cringey moment, a real zebra was donated to the San Francisco Zoo by the drug’s manufacturer, and ceremonially named … Max. What else?
Patients (and their parents) loved the Z-Pak. Compared with antibiotics that came with frequent dosing and frequent side effects and difficult-to-open plastic bottles, the Z-Pak felt so efficient.
Add the rise of patient-satisfaction metrics to go along with the advertising, and a health care system increasingly optimized for speed and convenience, and azithromycin found itself perfectly positioned. It became the antibiotic people expected (and asked for by name — I want a Z-Pak!), and clinicians reached for reflexively.
That dynamic has only intensified in the modern era, particularly with the expansion of telehealth. Final “true story” of this post: During the pandemic, a physician colleague of mine shifted to doing exclusively telehealth for a large national company — a model that suited him well, allowing him to travel freely and spend time with grandchildren scattered across the country, mostly in warmer climates.
When I asked him which antibiotic he prescribed most often in these virtual encounters, his answer was instantaneous: azithromycin. In settings where the examination is limited, diagnostic testing is unavailable, and the encounter is brief, the Z-Pak becomes the path of least resistance.
That convenience helps explain how azithromycin came to dominate outpatient prescribing. Whether that dominance has come at a cost will be the subject of Part 2, despite the fact that I have already written far more words about the Z-Pak than I ever imagined possible.
(Source of vintage zebra image at top: publicdomainimages.net.)