Azithromycin (Zithromax®) Being Tested Against Coronavirus…

This is not the logo for Pfizer Zithromax®, but it is intended to remind you of it, and of Pfizer’s Z-Pak product.

COVID-19 Z-Pak may be in your future! It hasn’t yet been proven – but if it turns out to be important, you might have heard it here first.

The Desperate Scramble to Fight Coronavirus

The number of scientists working to conquer COVID-19 coronavirus is staggering. A Google search on COVID-19 journal articles produces – brace yourself – 1.3 million hits! People are trying everything they can possibly think of to cure, soften, prevent, or help those suffering from the disease.

Among the things doctors are trying are medicines that work against other diseases, and that we know to be safe. However, when everyone tries everything, sometimes they will miss the boat. In other words, when you kiss a frog, it’s not always a prince.

The most notorious failure seems to be the drug hydroxychloroquine (HCQ). Doctors know HCQ as a treatment for arthritis and for prevention of malaria. A small study in France reported favorable results. However, that study was seriously flawed and later, more careful trials have thus far not identified any benefit from the drug.

Today’s blog is about another time-honored medicine, azithromycin. Ironically, the faulty HCQ study also used azithromycin, which seemed to help.

Is azithromycin potentially a prince, or merely one more frog? Well, your doctor will not prescribe azithromycin (it is contraindicated) if you have certain heart irregularities (prolonged QTc interval), you should not take it with HCQ, nor should you take it if you are sensitive to this type of antibiotic. However, when these factors don’t pose a problem, researchers believe that azithromycin is worth studying to counter COVID-19.

If you feel the need to jump forward to the major sections below, bless your enthusiasm! Here are your links:

A Possible Mechanism for Z-Pak Effectiveness

COVID-19 Disease Progression

Clinical Trials on COVID-19 Z-Pak

Doctors Are Not Waiting

            COVID-19 Z-Pak? Seems Unlikely

Azithromycin is often prescribed as a Z-Pak. Z-Pak is made by Pfizer, whose trademarked name for azithromycin is Zithromax®.

Z-Pak consists of a five day regimen of azithromycin capsules: 500 mg the first day, and 250 mg each of the following four days. In generic form, it is very affordable: my GoodRx app tells me that one generic Z-Pak would cost between $5 and $15 at my local pharmacies.

Azithromycin is an unlikely candidate to defeat coronavirus. Azithromycin is an antibiotic, and antibiotics are not generally considered effective against viruses. But after I finish this story I think you will stroke your chin and say, well, maybe… And perhaps, you’ll feel that there is hope to conquer COVID-19, after all.

            Dr P’s Circumstantial Evidence for COVID-19 Z-Pak

My tale begins with one of my doctors, a mature gentleman whom I will call Dr P.

Dr P told me that his son took a trip out of state with his business partner. While traveling, the partner came down with a severe continuing cough. Dr P phoned a pharmacy and gave him a prescription for Z-Pak.

After 5 days, the partner still had the cough. Over the years, Dr P has used Z-Pak with many patients to quell respiratory infections and prevent pneumonia. It’s his experience that usually one five-day dose is sufficient, but once in a while it takes two. So he renewed the prescription on condition that the infected man would go see a doctor, in case he had something more serious.

As it happens, the second Z-Pak cured the cough. The patient never did see a doctor. However, Dr P’s son then came down with a similar cough. Dr P came to the rescue again with a Z-Pak prescription. And in this case a single prescription banished the cough.

Because the US has such a well-publicized problem with coronavirus, Dr P could not resist. So he persuaded his son to take a coronavirus antibody test. The test was positive, indicating that the son had recovered from a coronavirus infection. He had not experienced any relevant symptoms previously, so Dr P inferred that the Z-Pak may have helped the son recover from a case of coronavirus.

A Possible Mechanism for Z-Pak Effectiveness

When I heard Dr P’s story I was consumed with curiosity. How could an antibiotic have any effect on a virus?

I could only think of one possibility. Each of us carries a variety of hostile microorganisms, viral and bacterial. Our immune system normally keeps these under control, so they don’t multiply enough to threaten our health.

If we catch a coronavirus infection, our immune system mobilizes to destroy it. However, if it is simultaneously fighting other bugs, those may interfere with our ability to shrug off COVID-19. Therefore, at the right time in the course of a coronavirus infection, an antibiotic might help tremendously, by removing distractions that keep the immune system from doing its best.

            Sorry, Art Isn’t That Kind of Doctor…

I’ve given you my speculation, but as a physicist my knowledge base is pretty far from medicine. So, what do the “real” doctors say? They say that I’m right, but only half right, because Z-Pak’s antibacterial effect is only part of the story. To better explain, here is a relevant graphic:

COVID-19 Disease Progression

COVID-19 Disease Progression

This diagram is a simple summary of the COVID-19 disease; its contents rely on four references given at the end of this blog. I created it for the benefit of a potential patient, not for a physician. The abscissa (horizontal axis) shows the time in days for the evolution of the infection. The time is approximate: for example, 5 days is only an average incubation time, which for different individuals may range from 2 to 14 days.

The patient may be infectious from day 1, but the first symptoms appear at the end of the incubation period. If the disease continues to progress, the virus replicates within the body during the next week.

Around 12 days after infection, the “pulmonary phase” begins, marked by shortness of breath and lack of oxygen in the tissues. The body shows increasing inflammation, and if the disease continues the symptoms become life-threatening.

            COVID-19 Z-Pak’s Possible Actions

My guesswork said that Z-Pak might help the body fight the coronavirus by suppressing bacteria that might be causing trouble at the same time as the virus. And the experts concur with that idea. Dr Catherine Oldenburg of UC San Francisco says, “A course of azithromycin or a dose of azithromycin could reduce other bacterial loads in patients who are presenting with both [COVID-19] and a bacterial pneumonia.” This idea and the diagram above suggest that Z-Pak could help an infected patient during the first week or two after infection.

A Scientific American blog goes farther, saying “a significant number of hospitalized COVID-19 patients have and are continuing to develop dangerous secondary bacterial co-infections such as bacterial pneumonia and sepsis.” In other words, you might not have had a bacterial infection when you first caught the COVID virus, but you may develop one along the way.

And, there’s more. A UK research team points out that azithromycin modulates the immune system, helping to fight inflammation; thus doctors often use it to fight chronic inflammatory lung diseases. And inflammation is a strong hallmark of advanced COVID-19 disease.

            Azithromycin Also Fights Viruses

However, even that is not the entire story. A French research group states “It has been shown that AZM [azithromycin] has significant antiviral properties. In contrast with CQ or HCQ, its antiviral activity has been shown in vitro and/or in vivo on a large panel of viruses: Ebola, Zika, respiratory syncytial virus, influenzae H1N1 virus, enterovirus, and rhinovirus.”

To summarize all of this, azithromycin potentially fights coronavirus on many fronts:

• Suppressing accompanying or secondary infection
• Fighting inflammation
• Weakening the virus itself

These are strong reasons why COVID-19 Z-Pak might be a worthwhile treatment.

I did some research and discovered that azithromycin is the subject of serious study as a treatment for coronavirus infection. You may be surprised at the scope of effort that exists, which I will now summarize.

Clinical Trials on COVID-19 Z-Pak

There are two significant ongoing studies of azithromycin as a treatment for COVID-19. The following factors are the same in these two trials:

• They study patients whom they believe to have an active case of COVID-19, based on testing or symptoms.
• The trials administer either a drug or a placebo, using a double-blind protocol.
• They exclude patients who are contraindicated (as described above) from taking azithromycin.

            Details of Two Large Ongoing Trials

The ACTION trial:

• The University of California San Francisco is conducting this trial.
• Sponsors include the Bill and Melinda Gates Foundation, Pfizer and Stanford University.
• The trial hopes to enlist at least 2,500 participants.
• Each patient will receive either a single 1200 mg dose of azithromycin or a placebo.
• The researchers will measure many factors, the principal one being whether the test subject went to a hospital for over 24 hours within 14 days after taking the drug or placebo.

The RECOVERY trial:

• The University of Oxford is leading this trial, with participating hospitals across UK.
• Sponsors include the UK National Institute for Health Research, the Wellcome Trust, the Bill and Melinda Gates Foundation, Health Data Research UK and the Medical Research Council Population Health Research Unit.
• The trial hopes for 15,000 participants. This seems like a large number of patients, but the study divides them into separate groups to look at a number of different drugs. In addition to azithromycin, the study is currently looking at corticosteroids, intravenous immunoglobulin, plasma from convalescent COVID patients and tocilizumab. (The trial originally included dexamethasone, HCQ and ritonavir/lopinavir. It showed that dexamethasone helped patients requiring mechanical ventilation or oxygen. Therefore, dexamethasone became a standard treatment and the trial stopped looking at it. The latter two drugs did not help patients and therefore the study managers deleted them.)
• Patients taking azithromycin will receive 500mg once daily for 10 days.
• The principal measures are death, discharge, need for ventilation and need for renal replacement therapy within 28 days of taking the medication or placebo.

Note added February 9, 2021: The RECOVERY trial has concluded that azithromycin does not benefit patients hospitalized with COVID-19. Therefore, if azithromycin has a role to play in treating COVID-19, it would be in the early stages of the disease, prior to hospitalization. RECOVERY has now stopped studying this option for hospitalized patients.

Since each of these trials involves thousands of COVID-infected patients, the resulting data should be fairly convincing, whether it is positive or negative.

Doctors Are Not Waiting

However, physicians are not waiting for the clinical trials to finish. They recognize that azithromycin is very safe (provided you don’t have the contraindications discussed earlier) and that it might help a COVID-infected patient. Therefore, not only Dr P but also other doctors are already using COVID-19 Z-Pak treatment on patients who may have coronavirus infections. Here is what I found:

• Some healthcare organizations develop protocols to guide their physicians in treating new and difficult diseases. Eastern Virginia Medical School has issued a comprehensive guide to treating coronavirus beginning with its first symptoms. One of the “additional treatment components” they suggest is a regimen of azithromycin which exactly duplicates a Z-Pak treatment. They comment that azithromycin “has immunomodulating properties including downregulating IL-6; has anti-viral properties and in addition, Rx of concomitant bacterial pneumonia.”
• Schwartz and Suskind published a strong recommendation to try COVID Z-Pak treatment at first signs of coronavirus in both adults and children. In his own practice, Dr Schwartz has used Z-Pak to treat more than 50 patients who exhibited flu-like symptoms, including two older women who tested positive for coronavirus. All of the patients improved quickly and did not require hospitalization. He did not give this therapy to patients with a “history of liver disease, heart disease, or allergies to azithromycin, erythromycin, or any other macrolides.”

Considering both the clinical trials and its informal use by physicians, it seems possible that COVID-19 Z-Pak may become one of the accepted treatments for coronavirus during the coming few months.

            An Apparently Contrary Point of View

This is a good place to call attention to one research paper whose title caught my eye: “Azithromycin Should Not Be Used to Treat COVID-19” by Lighter and Raabe. When I examined the article, it questioned whether azithromycin would have any significant antiviral or anti-inflammatory effect against COVID-19. Apart from that quibble, however, the article did not address azithromycin as a stand-alone therapy.

The authors’ main purpose was to discourage the use of azithromycin in conjunction with hydroxychloroquine therapy. And other experts such as those conducting the ACTION and RECOVERY trials agree that doctors should not use azithromycin if the patient is also receiving hydroxychloroquine.

I concluded that the title of Lighter and Raabe’s article was overly broad and not an accurate description of the authors’ principal arguments. Therefore, the terrifying title is not in itself a sufficient reason to dismiss COVID-19 Z-Pak therapy as a possibly useful approach against coronavirus.

This blog has been, once again, an attempt to help my readers learn the news before it’s news: in this case, to be aware that COVID-19 Z-Pak therapy may become a safe, effective and affordable way to bring coronavirus under control. I hope that you don’t catch it! However, if you do, I hope that this information will help you better understand your potential options for treatment.

Image Credits:
– Newly invented fake azithromycin logo by Art Chester
– Diagram by Art Chester based on information from EVMS Critical Care Protocol, Hasan Siddiqi & Mandeep Mehra, Salim Rezaie and FDA Coronavirus Fact Sheet