What is the truth about Zithromax?

It was during my residency that the first indication of heart toxicity of antibiotics affected me personally.  The threat was related to the use of the first of the non-drowsy antihistamines – Seldane – in combination with macrolide antibiotics, such as Erythromycin causing a potentially fatal heart arrhythmia.  I remember the expressions fear from other residents, as we had used this combination of medications often.  Were we killing people when we treated their bronchitis?  We had no idea, but we were consoled by the fact that the people who had gotten our arrhythmia-provoking combo were largely anonymous to us (ER patients).

Fast forward to 2012 and the study (published in the holy writings of the New England Journal of Medicine) that Zithromax is associated with more dead people than no Zithromax.  Here’s the headline-provoking conclusion:

During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002).  Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. (Emphasis Mine).

It turns out that they also indicted Levofloxacin, another commonly-used antibiotic as being roughly as risky as Zithromax.

While this is good fodder for the headlines, it hits me right where I live.  I constantly have patients coming into the office with symptoms that make them feel they need an antibiotic, many of whom have gotten Zithromax.  I wrote an early post on the subject of the temptation to give a Z-Pak in the gift basket we give our patients for walking into our office:

Which brings me back to the Z-Pak.  Zithromax (Azithromycin) is truly a great drug, and the friend of many doctors.  It treats strep throat, skin infections, sexually transmitted disease, whooping cough, and certain kinds of, yes, bronchitis.  It is very easy to take, requiring a total of 5 doses over 5 days, and it comes in a handy-dandy pack with a catchy name.  When a patient tells their friends and family, “I got a Z-Pak,” they are much more impressed than if they say, “I got an antibiotic.”

I ended with a warning:

So, when you have a cough and go to the doctor, get the diagnosis of bronchitis, and get a Z-Pak think of me.  You may want to ask if you really need the antibiotic, or if you can wait to see if it will go away without it.  In many, if not most cases, you might just as well meditate with the word “Zithromax” as your mantra, or burn the pills in a sacrifice to the Greek god Z-pacchus.

God bless America, land of the Z.

I even wrote a poem for it:

Six little pills at the patients’ insistence
Six little pills should we now keep our distance?
Six little pills we’ll rue your existence
If Six little pills are paths to resistance.

Oh Zithromax, Zithromax!
You make us desirous
Against our best judgment to cover a virus
Oh Zithromax, Zithromax!
Your pills in a pack
So oft make the best doctor act like a quack.

Yet there are good reasons to use antibiotics like Zithromax, so I am left with the dilemma of how to interpret the results.  Is this a real problem, or is it simply a retrospective study by a bunch of scientists wanting to make a splash?  I have to answer this question because I have to decide whether or not I am going to write a prescription for this medication, risking a “is my doctor trying to kill me?” look from my patients.  I have to prescribe antibiotics, but in doing so do I feed the fortunes of personal injury attorneys who realize the two following things:

  1. Doctors prescribe Zithromax by the bucket
  2. Every one of the patients who get a Zithromax prescription will die.

I give it 2 weeks before we see a commercial soliciting business for people who have loved ones who took Zithromax and then had heart attacks.

To figure out how to deal with this dilemma, I went to some of the experts among the med blogger community.  Marya Zilberberg is an epidemiologist at the University of Massachusetts and author of the blog, Healthcare, etc.  She even wrote a book about how to properly read medical literature (a book that I need to read, actually).  In short, she’s brainy.  She wrote a post entitled, Why I have the propensity to believe the azythromycin data (I told you she was brainy), in which she states the following:

But there is a second, possibly more important reason that I am inclined to believe the data. The reason is called succinctly “propensity scoring.” This is the technique that the investigators used to adjust away as much as feasible the possibility that factors other than the exposure to the drug caused the observed effect.

She then quotes a part of her book (which I definitely need to read) about propensity scoring.  Tying this to the Zithromax study:

And if you are able to access Table 1 of the paper, you will see that their propensity matching was spectacularly successful. So, although it does not eliminate the possibility that something unobserved or unmeasured is causing this increase in deaths, the meticulous methods used lower the probability of this.

So by this I am led to believe the data have some beef behind them.  I am also much more likely to use the word “propensity,” as it may make me sound as brainy as Marya.

On the counterpoint is Dr. Wes, one of the old guard bloggers (who I’ve drunk beer with), who has been blogging since the internet was run by carrier pigeon.  Dr. Wes is a cardiologist who specializes in heart rhythm problems, the kind of problems that presumably killed the people in the NEJM study.  He wrote an article, How Bad is Azithromycin’s Cardiovascular Risk?  in which he admits the potential risk of this kind of antibiotics, but questions the data methods of the study:

What was far scarier to me, though, was how the authors of this week’s paper reached their estimates of the magnitude of azithromycin’s cardiovascular risk.

Welcome to the underworld of Big Data Medicine.

He minces no words as he continues:

To think that despite all of the confounding factors that the authors had the balls to state that “as compared with amoxacillin that there were 47 additional deaths per 1 million courses of azithromycin therapy; for patients with the highest decile of baseline risk of cardiovascular disease, there were 245 additional cardiovascular deaths per 1 million courses” is ridiculous.  Seriously, after all the manipulation of data, they are capable of defining a magnitude to three significant digits out of a million of anything?

His conclusion is that this study is basically a bunch of sensationalized data meant to get headlines (which it did).  I think he needs a beer.  Call me, Wes.

So I am left to sift through these two opinions of two people I respect, and do so in the backdrop of patients wanting antibiotics and lawyers dreaming of big yachts.  What do I think?  I think we can’t tell what the truth really is.  Yes, the folks who wrote the study are probably gunning for headlines (as is the NEJM), but it is also a fact that antibiotics can be dangerous, and all drugs come with some sort of a price.

I come back to advice I gave in an earlier post: When all else fails, do nothing.  Don’t give an antibiotic unless it’s needed, and don’t ask for one if you don’t need it.

Rob Lamberts is an internal medicine-pediatrics physician who blogs at More Musings (of a Distractible Kind).

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