How the Z-Pak Took Over Outpatient Medicine, Part 2: The Reckoning

Part 1 of this azithromycin series explained how the drug became ubiquitous. In Part 2, we’ll explore why many of us infectious diseases physicians now groan when they hear the words, “They already started a Z-Pak.” Because what began as a genuine pharmacologic advance became, through sheer volume of use, an antibiotic that doesn’t work very well, yet can still cause side effects and muddy diagnostic waters (and cause groans).

Here are the problems — some specific to azithromycin itself, and some due mostly to its sheer popularity, because otherwise these problems are shared with any indiscriminate use of outpatient antibiotics.

Please stick around to the end, because I’ll finish with some clinical indications for azithromycin where it remains arguably the drug of choice.

Bacterial Resistance, or The Bugs are Smarter Than We Are

The biggest problem with azithromycin overuse is also the most obvious: resistance, which emerged quickly among common respiratory pathogens. Macrolide resistance in Streptococcus pneumoniae is now widespread, with rates in many regions high enough to make empiric use difficult to justify. Resistance in Haemophilus influenzae is lower but has also increased steadily over time.

Even Mycoplasma pneumoniae — once reliably susceptible — has developed striking resistance in parts of Asia, where 80–90% of isolates are now macrolide resistant.

And Streptococcus pyogenes, the cause of strep throat, is no longer consistently treated with macrolides. Azithromycin susceptibility is unpredictable, with resistance rates varying widely by region and occasionally rising with alarming speed. Since most clinical sites don’t do routine susceptibilities on strep, it’s a guessing game whether azithromycin will work for this indication.

Notably, this shift has already been reflected in practice guidelines. Major recommendations for outpatient respiratory infections have steadily moved away from macrolide monotherapy in most settings — an acknowledgment that resistance has eroded azithromycin’s reliability for empiric treatment.

Induction of Culture Negativity

Is that the right term? Here’s the scenario, you decide:

A 75-year-old man with a history of aortic valve replacement starts feeling tired. Shortly thereafter, he notes a little low-grade fever and loss of appetite. He’s convinced he’s coming down with something because he’d just spent a busy holiday weekend with his three grandchildren — toddler twins and a 5-year-old in daycare, all of whom have some sort of respiratory crud.

So he dials up his favorite online telehealth service, gives the above history including the three sniffly, coughing kids, receives a prescription for a Z-Pak, and clicks the 5 (out of 5) rating for user feedback before signing off.

The problem? This illness could well be bacterial endocarditis, commonly caused by strep and staph, many of which are susceptible to azithromycin. A few days of empiric treatment is just enough to turn blood cultures negative, but clearly not sufficient for treatment.

So if you wonder why we ID doctors groan at the “already started a Z-Pak” history, one reason is that culture-negative endocarditis — and related “culture-negative” cases — are some of our most challenging ID consults.

Diagnostic Confusion or Misdirection

The most common issue is that someone gets a viral respiratory tract infection, gets a Z-Pak, gets better, and assumes it was the antibiotic that did it. In the minds of some of our patients, that’s a powerful reinforcement loop that no randomized trial can ever fully undo.

Which reminds me to emphasize that there has been a double-blind, clinical trial of azithromycin (vs. vitamin C) in outpatient bronchitis. Take a look at one of the most important endpoints, “Proportion of patients who had returned to their usual daily activities.”

If you prefer the result in movie comedy form, this is for you:

That’s right, nearly (but not quite) identical — in statistical terms, we call this “not significant”.

A different problem arises with Fusobacterium necrophorum, the bug with a scary name and the most common cause of septic jugular vein thrombosis, or the dreaded Lemierre’s syndrome. Occurring predominantly in teens and young adults, Lemierre’s can take a previously healthy kid and put them in an ICU with critical illness — and azithromycin isn’t active against F. necrophorum, while beta-lactam antibiotics have excellent activity. This can lead to a dangerous delay in diagnosis.

Here’s how the story typically unfolds:

1. 19-year-old college student with a vague history of penicillin allergy goes to university health service with a bad sore throat.
2. Rapid strep negative; told to go home and rest, it’s a viral URI. [Important note: This may well be true at the outset!]
3. They come back with worse symptoms. Work-up for mono negative.
4. Empiric azithromycin prescribed, not penicillin or cephalexin, because of that penicillin allergy.
5. Waits a few days to see if the azithromycin works, but develops even higher fever, neck and chest pain, shortness of breath.
6. Goes to emergency room where evaluation shows jugular vein thrombosis and septic pulmonary emboli.
7. Blood cultures grow Fusobacterium necrophorum, less commonly other oral bacteria.
8. Experiences a prolonged hospital stay requiring intravenous antibiotics, anticoagulation, and sometimes further complications.

As I said, scary. Admittedly, it’s rare, but Lemierre’s definitely happens; azithromycin isn’t the culprit, but it can act as a prelude to delay diagnosis and the start of effective therapy.

Side Effects

All antibiotics have gastrointestinal side effects by altering the normal microbiome. But macrolide antibiotics, even azithromycin, act as agonists on the intestinal peptide motilin to stimulate gut activity, which can cause cramping and diarrhea. Little-known fact — this off-target prokinetic effect means erythromycin (remember that?) can be used as a treatment of gastroparesis and select cases of chronic intestinal pseudo-obstruction.

QT prolongation is another signature side effect of macrolide antibiotics. While azithromycin has the lowest tendency, it remains a problem in particular for patients taking other QT-prolonging agents and those with underlying cardiac conduction disorders. And some (but not all) population-based studies have linked azithromycin use to an increased risk of cardiovascular events.

All Right, Enough Already — When Should We Use Azithromycin?

Despite all of the above, azithromycin remains an important antibiotic when used for the right indications. There are several settings in which azithromycin remains clearly useful, and in some cases essential.

1. Azithromycin continues to play an important role in the treatment of certain sexually transmitted infections, either as first-line therapy or as part of combination regimens, depending on the pathogen and local resistance patterns.
2. Azithromycin remains a key agent for infections caused by Mycoplasma pneumoniae when susceptibility can reasonably be assumed, particularly outside regions where macrolide resistance is now common. It’s why we still see it as part of combination therapy for people admitted to the hospital for community-acquired pneumonia, as it also has activity against Legionella species and Chlamydia pneumoniae — and beta-lactams don’t.
3. Most critically, azithromycin is indispensable in the treatment of nontuberculous mycobacterial (NTM) infections, especially Mycobacterium avium complex (MAC) and Mycobacterium abscessus. The distinction between macrolide-susceptible and macrolide-resistant isolates carries enormous prognostic significance.

Ok, I’m done now — enough about azithromycin, good and bad. Hope you enjoyed this journey! Reminds me of the ID doctor who started their note with “Briefly, …” and then went on for 2000 words. (Actually, over 2500.)

We can’t help ourselves!

And thanks to Dr. Ryan Christianson, who alerted me to this television commercial, which amazingly sponsored Sesame Street in 2001.

(Source of zebra image at top: PublicDomainPictures.net)