Novel Drug Combinations for Lyme Persister Cells: What Researchers Found

Laboratory studies identified drugs active against Lyme persister cells
Round body forms may respond differently to antibiotics
Clinical relevance remains uncertain

In a study entitled A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library, Feng and colleagues hypothesized that when Borrelia burgdorferi, the Lyme bacterium, is confronted with stressors such as starvation or antibiotic exposure, the spirochete can transform into a round body or persister form. These morphologic variants appeared more tolerant to standard antibiotics in laboratory models.

Importantly, these findings are based primarily on in vitro models. Laboratory activity does not necessarily translate into improved outcomes in humans, and the significance of persister forms remains debated.

Questions surrounding persisters overlap with broader discussions about persistent Lyme disease mechanisms and ongoing symptom development.

“It is most likely that a single drug may not effectively kill all bacterial populations including morphological variants,” states Feng. Investigators found that antibiotic tolerance increased as morphology shifted from actively growing spirochetes toward round body and microcolony forms.

What are Lyme persister cells?

Researchers use the term persister cells to describe bacterial populations that appear less susceptible to antibiotics under laboratory conditions.

In these studies, investigators induced round body forms using amoxicillin exposure and examined whether different drugs showed improved activity.

The importance of these forms in human disease remains uncertain.

Which drug combinations showed activity in vitro?

Combination therapy containing daptomycin appeared most active in laboratory experiments.

Investigators reported that daptomycin plus doxycycline and cefoperazone eradicated resistant microcolony forms in laboratory cultures and prevented regrowth during subculture experiments. These findings have not established effectiveness in human disease.

Researchers also identified 23 compounds with activity against round body forms. Examples included:

• Artemisinin
• Ciprofloxacin
• Nifuroxime
• Fosfomycin
• Chlortetracycline
• Sulfacetamide
• Sulfamethoxypyridazine
• Sulfathiazole
• Clofazimine

Most of these observations come from laboratory models and should not be interpreted as proof of clinical effectiveness.

Why are fosfomycin, ciprofloxacin, and artemisinin attracting attention?

Several drugs identified in laboratory studies are already approved for unrelated conditions, which has increased interest in whether existing medications could affect Borrelia persister forms.

Fosfomycin

Fosfomycin is available in the United States, most commonly as oral fosfomycin tromethamine for uncomplicated urinary tract infections caused by susceptible bacteria such as E. coli.

Laboratory studies identified activity against Borrelia forms, but these findings have not established a role for fosfomycin in routine Lyme disease treatment.

Ciprofloxacin

Ciprofloxacin demonstrated laboratory activity in persister models but is not typically considered a first-line Lyme disease treatment.

Fluoroquinolones such as ciprofloxacin carry important safety concerns including tendon injury, neuropathy, central nervous system effects, and rare vascular complications, which may limit use in many patients.

Artemisinin

Artemisinin demonstrated activity in laboratory screening studies and has also generated interest because of its use in some antiparasitic treatment strategies.

Questions about artemisinin often overlap with discussions surrounding Babesia and related coinfections, but laboratory findings alone do not establish effectiveness against Lyme disease.

Other compounds including nifuroxime, chlortetracycline, and clofazimine also demonstrated laboratory activity, though their clinical relevance for Lyme disease remains uncertain.

Questions about antibiotics frequently overlap with broader discussions surrounding tick-borne coinfections, antibiotic selection, and persistent symptoms.

Do round body forms matter clinically?

Researchers remain divided over whether morphologic variants contribute meaningfully to persistent symptoms.

Feng and colleagues note that round body forms have been described in human tissue studies, including brain tissue. However, the biologic significance remains unclear.

Other investigators have questioned whether morphologic variants play an important role in chronic disease mechanisms.

These questions overlap with broader diagnostic uncertainty seen in Lyme disease testing limitations.

What are the limitations of these findings?

• Most evidence comes from laboratory studies
• Human clinical trials remain limited
• Drug activity in vitro may not predict clinical benefit
• The role of persister forms remains debated
• Optimal combinations and durations remain unknown

Frequently Asked Questions

What are Lyme persister cells?

Persister cells are bacterial forms that appear more tolerant to antibiotics under laboratory conditions.

Is fosfomycin used for Lyme disease?

Fosfomycin showed laboratory activity against Borrelia forms but is primarily approved for urinary tract infections.

Is fosfomycin a sulfa drug?

No. Fosfomycin is not classified as a sulfonamide antibiotic.

Does ciprofloxacin treat Lyme disease?

Ciprofloxacin demonstrated activity in laboratory models but is not typically considered a first-line Lyme disease therapy.

Are round body forms important in Lyme disease?

The importance of round body forms remains debated and has not been fully established in human disease.

Clinical Takeaway

Laboratory studies suggest some drug combinations may have activity against Borrelia morphologic variants, but translating laboratory findings into clinical practice remains challenging.

Current evidence supports continued research into persister biology while recognizing that in vitro activity alone does not establish effective patient treatment.

Related Articles

These articles explore persistent symptoms, mechanisms, and treatment challenges in Lyme disease.

Persistent Lyme disease mechanisms
Persistent Lyme disease overview
Round bodies, blebs and biofilms in Lyme disease
Delayed Lyme disease diagnosis
Recovery from Lyme disease

References

1. Feng J, Shi W, Miklossy J, Tauxe GM, McMeniman CJ, Zhang Y. Identification of Additional Anti-Persister Activity against Borrelia burgdorferi from an FDA Drug Library. Antibiotics (Basel). 2015;4(3):397-410.
2. Feng J, Wang T, Shi W, Zhang S, Sullivan D, Auwaerter PG, Zhang Y. A Drug Combination Screen Identifies Drugs Active against Amoxicillin-Induced Round Bodies of In Vitro Borrelia burgdorferi Persisters from an FDA Drug Library. Front Microbiol. 2016;7:743.
3. 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.
4. Miklossy J, Kasas S, Zurn AD, McCall S, Yu S, McGeer PL. Persisting atypical and cystic forms of Borrelia burgdorferi and local inflammation in Lyme neuroborreliosis. J Neuroinflammation. 2008;5:40.
5. Lantos PM, Auwaerter PG, Wormser GP. A systematic review of Borrelia burgdorferi morphologic variants does not support a role in chronic Lyme disease. Clin Infect Dis. 2014;58(5):663-671.

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Dr. Daniel Cameron, MD, MPH
Lyme disease clinician with over 30 years of experience and past president of ILADS.

Symptoms • Testing • Coinfections • Recovery • Pediatric • Prevention