How to Treat Persister Lyme. What Works?

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Persister Lyme in a Lyme disease treatment image from Marty Ross MD

About Persister Lyme

Lyme disease is difficult to treat. While a majority of people with acute Lyme do get better following the standard one to two months of antibiotics recommended by the US Centers for Disease Control and Prevention (CDC) and the Infectious Diseases Society of America (IDSA), many do not. In particular, if Lyme treatment starts more than a month or so after the acute infection, it appears more difficult to treat.

There are a number of reasons Lyme is hard to treat. One idea getting a lot of current attention is that Lyme, like tuberculosis and leprosy, can develop persister cells. Persisters in Lyme are comprised of the spirochetes, cysts, and biofilm communities that grow very slowly or not at all. These persister forms essentially go into hibernation where they ignore the antibiotics a person takes and the immune system.

In this article, I review a number of ways to treat persister Lyme. These treatment approaches are based on

  • the ground-breaking research of Lewis and colleagues at Northeastern University in Boston published in 2015 showing that Lyme develops persisters,
  • the growing work of Ying Zhang, MD, at John's Hopkins University in Baltimore who is discovering combinations of antibiotics to treat persisters, and
  • the clinical research of Richard Horowitz, MD, using the leprosy antibiotic dapsone, out of his practice in New York state.

In addition, one of the older approaches I used when I practiced in Seattle—using a very long pulse regimen—is inspired from the clinical experience of the Lyme treatment pioneer, Joseph Burrascano, MD.

Marty Ross Discusses Lyme Persister Treatments 


The Northeastern University Studies

In 2015, Lewis and colleagues showed Lyme developed persister cells when exposed to ongoing antibiotics. More importantly, their laboratory science studies showed that once antibiotics are stopped, the germs move out of persister hibernation back into a growth phase that responds to antibiotics again. In Lewis' experiments, starting and stopping antibiotics four times killed all forms of Lyme.

Another key finding is Lyme does not develop antibiotic resistance by starting and stopping antibiotics. Most bacteria learn resistance to an antibiotic through genetic mechanisms when antibiotics are started and stopped, but this does not happen in Lyme persisters. So, a persister cell or state is not the same as drug resistance. In a slowed-growth persister state, Lyme just simply ignores the antibiotics.

Zhang Studies

Zhang comes to the world of Lyme from the world of tuberculosis research. Like Lyme, tuberculosis develops persister cells, too. In tuberculosis, multiple drug regimens work best to target persistence. Zhang is bringing that idea to the world of his Lyme persister research. He has done a number of experiments finding different antibiotic combinations that can treat persister Lyme. The problem with his work is that most of the combinations of antibiotics he has found effective are not accessible to the average person. Either the drug combinations he found to be effective are very costly, certain medications are only available for certain diseases, or the drugs are not available in the USA.

For instance, one of the promising combinations is daptomycin, cefoperazone, and doxycycline. The daptomycin is approved for skin infections in IV form and is very expensive. It is unlikely any insurance company would pay for it in a Lyme treatment based on Zhang's lab experiments. Additionally, the cefoperazone is not available in the USA.

There is one combination that Zhang proposes that is available. It includes cefuroxime, doxycycline, and Bactrim DS. In the combination

  • cefuroxime blocks the repair of Lyme spirochete cell walls in growing and persister Lyme,
  • Bactrim DS likely damages the DNA of persister spirochetes and cysts, and
  • doxycycline blocks protein production in persister forms.

Horowitz Studies

Horowitz used various combinations of antibiotics and a leprosy antibiotic called dapsone to treat persister Lyme. Leprosy, like Lyme, has persister cells. In a study of 100 of Horowitz’s patients who had difficulty improving on other treatments and were given dapsone, 59 percent had improvements. Read more about the specifics of dapsone treatment and the chances of it helping in Dapsone for Lyme Persisters. A Miracle Antibiotic? 


Before leaving clinical practice in the early 2010s, Burrascano was treating patients by stopping antibiotics for long periods of time, allowing the patient to get sick. Then he would restart the antibiotics for a couple of months or so, long enough to see improvements and for Herxheimer reactions to disappear.

Burrascano hypothesized that after a period of time, Lyme ignored the antibiotics and stopped growing. During the off period, he let people get sick as a sign the germ was fully back into a growth state where antibiotics could kill it more effectively. Generally, his approach worked out to about two months off antibiotics and then two months on. He suggested the sicker a person let himself or herself become, the greater chance the antibiotics would work. He claims a cure with this method after four starting-and-stopping cycles.

When Burrasano came up with this idea, the work of Lewis and his colleagues at Northeastern was not complete. Yet, his idea is supported by Lewis' research that Lyme develops slow growing persister cells that stop responding to antibiotics. When antibiotics are stopped, they wake back up again and respond.

So What Works for Lyme Persisters?

When I treated patients, I used three different Lyme persister regimens. If one did not work after six to eight months, then I tried the next one. I

  • explained the three options to my patients and let them choose,
  • reserved these regimens for people who are over a year or more into treatment, for which nothing else has helped, or who are still very ill with limited improvements, and
  • tried the approaches outlined in the chapter Can't Get Better? Do This.

The following are the three options.

Option 1. A Horowitz Dapsone Approach

To see this full approach, including the steps to prevent side effects and limit Herxheimer reactions, read Dapsone for Lyme Persisters. A Miracle Antibiotic? This approach helps 59 percent of people to get various degrees of improvement, but it is a very harsh treatment at times. As a result, 30 percent of people have to stop taking the medication. And yet, I have seen some wonderful improvements on this regimen.

Option 2. A Zhang Approach

I prescribed the three-drug combination of cefuroxime, doxycycline, and Bactrim DS mentioned above. To this, I added grapefruit seed extract for better Lyme cyst coverage. I found this combination helpful 50 percent of the time with various degrees of improvements. I did not seen someone get very well on this regimen like I did see with a Horowitz protocol or a Burrascano approach mentioned below. But I only offered this approach for a year before I stopped clinical practice.

  • Cefuroxime 500 mg 1 pill 2 times a day
  • Doxycycline 100 mg 1 pill 2 times a day
  • Bactrim DS 1 pill 2 times a day
  • Grapefruit Seed Extract 250 mg 1 pill 2 times a day. This is a supplement.

Option 3. A Burrascano Protocol

I used a number of antibiotic combinations like those mentioned in A Lyme Disease Antibiotic Guide. I used them for two months off, then two months on. Sometimes I used them for one month on or one month off. I saw this approach help about 50 percent of the time with various degrees of improvements. Unlike Burrascano, I do not believe these cure people. However, I have seen a number of my patients who remained quite ill after antibiotics get very well on this approach.

New Ideas

As I mentioned above, Zhang continues experiments to identify drugs and supplements to treat persister Lyme. He has identified the malarial and Babesia herbal antibiotic called Artemisinin as an agent that can disrupt the Lyme cell membrane. Some of his latest work also shows that oregano oil and a variety of other essential oils can can treat persisters. Read about my thoughts on essential oils for persister Lyme in Essential Oils for Persister Lyme May Help.

There is one other new idea. There is some promising early research and clinical experience showing that the alcohol treatment drug called Antabuse (disulfiram) may be an effective persister Lyme treatment. Read more about this in Is Antabuse (disulfiram) The Magic Bullet for Chronic Lyme Disease?


The ideas and recommendations on this website and in this article are for informational purposes only. For more information about this, see the sitewide Terms & Conditions.


View Citations

  1. Horowitz R, Freeman, PR. The use of dapsone as a novel “persister” drug in the treatment of chronic Lyme disease/post treatment Lyme disease syndrome. J Clin Exp Dermatol Res. 2016;7:3. doi: 10.4172/2155-9554.1000345. (View)
  2. Feng J, Auwaerter PG, Zhang Y. Drug combinations against Borrelia burgdorferi persisters in vitro: eradication achieved by using daptomycin, cefoperazone and doxycycline. PLoS ONE. 2015;10(3): e0117207. doi:10.1371/journal.pone.0117207. (View)
  3. Sharma B, Brown AV, Matluck NE, Hu LT, Lewis K. Borrelia burgdorferi, the causative agent of Lyme disease, forms drug-tolerant persister cells. Antimicrob Agents Chemother. 2016;59:4616–4624. doi:10.1128/AAC.00864-15. (View)
  4. Feng J, Zhang S, Shi W, Zubcevik N, Miklossy J, Zhang Y. Selective Essential Oils from Spice or Culinary Herbs Have High Activity against Stationary Phase and Biofilm Borrelia burgdorferi. Front Med (Lausanne). 2017;4:169. Published 2017 Oct 11. doi:10.3389/fmed.2017.00169 (View)
  5. Feng J, Shi W, Miklossy J, Tauxe GM, McMeniman CJ, Zhang Y. Identification of Essential Oils with Strong Activity against Stationary Phase Borrelia burgdorferi. Antibiotics (Basel). 2018;7(4):89. Published 2018 Oct 16. doi:10.3390/antibiotics7040089 (View)
  6. Pothineni VR, Wagh D, Babar MM, et al. Identification of new drug candidates against Borrelia burgdorferi using high-throughput screening. Drug Des Devel Ther. 2016;10:1307–1322. Published 2016 Apr 1. doi:10.2147/DDDT.S101486 (View)
  7. Liegner KB. Disulfiram (Tetraethylthiuram Disulfide) in the Treatment of Lyme Disease and Babesiosis: Report of Experience in Three Cases. Antibiotics (Basel). 2019;8(2):72. Published 2019 May 30. doi:10.3390/antibiotics8020072 (View)

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About the Author

Marty Ross, MD is a passionate Lyme disease educator and clinical expert. He helps Lyme sufferers and their physicians see what really works based on his review of the science and extensive real-world experience. Dr. Ross is licensed to practice medicine in Washington State where he has treated thousands of Lyme disease patients in his Seattle practice. 

Marty Ross, MD is a graduate of Indiana University School of Medicine and Georgetown University Family Medicine Residency. He is a member of the International Lyme and Associated Disease Society (ILADS) and The Institute for Functional Medicine.

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