Can Lyme Disease Bacteria Persist After Antibiotic Treatment?

How Lyme bacteria may tolerate antibiotics
What newer persistence research shows
Why the clinical implications remain uncertain

Can Lyme disease bacteria persist after antibiotic treatment? Laboratory and animal studies suggest that Borrelia burgdorferi can sometimes survive antibiotic exposure or enter antimicrobial-tolerant states. However, researchers have not established how often viable bacteria persist in treated patients or whether they explain ongoing symptoms.

Newer studies have made the persistence debate more nuanced. Some laboratory cells previously described as persisters may be too damaged to reproduce. Meanwhile, viable B. burgdorferi can survive for more than a year inside unfed ticks, biofilm growth can reduce antibiotic susceptibility in vitro, and bacterial cell-wall material may persist after the organisms have been cleared.

These findings point to several different biological possibilities—not one simple explanation for persistent illness.

What are bacterial persister cells?

Persister cells are a small subpopulation of bacteria that survive antibiotic exposure without necessarily acquiring genetic resistance. They may become metabolically inactive or slow-growing, making them less vulnerable to antibiotics that work best against actively dividing bacteria.

When conditions improve, true persister cells should be capable of resuming growth. This ability to recover and reproduce distinguishes viable persisters from damaged bacterial cells or persistent bacterial debris.

Cabello and colleagues described persistence as a widely accepted phenomenon in microbiology that may sometimes have therapeutic implications.¹ They proposed that survival programs used by B. burgdorferi throughout its tick–vertebrate lifecycle might also contribute to antibiotic tolerance.

In a 2022 review, Cabello and colleagues further examined antimicrobial-tolerant persistence as one possible contributor to Lyme disease and post-treatment Lyme disease syndrome. They emphasized that persistent symptoms are likely heterogeneous and that antimicrobial tolerance, immune responses, bacterial remnants, co-infections, and other mechanisms may interact.³

How might Lyme bacteria tolerate antibiotics?

B. burgdorferi must adapt to markedly different environments as it moves between ticks and vertebrate hosts. This requires changes in metabolism, gene expression, and surface proteins.

For example, outer surface protein A (OspA) is expressed predominantly while the spirochete is in the tick. Outer surface protein C (OspC) becomes particularly important during transmission and early infection of the vertebrate host.

Cabello and colleagues proposed that the stringent response—a bacterial survival program activated by nutrient deprivation and other stresses—may help B. burgdorferi survive throughout this enzootic cycle.¹

Potential mechanisms of antimicrobial tolerance include:

• Reduced metabolic activity
• Slower growth or temporary dormancy
• Changes in gene expression
• Altered bacterial forms
• Biofilm-like growth
• Residence in relatively protected tissue sites

These adaptations reflect phenotypic tolerance rather than conventional genetic antibiotic resistance.

Are stationary-phase Lyme bacteria true persisters?

Stationary-phase cultures have frequently been used to study Lyme disease persisters. These cultures contain bacteria that have stopped multiplying rapidly as nutrients become limited.

Earlier laboratory studies found that stationary-phase B. burgdorferi could tolerate antibiotics commonly used to treat Lyme disease, including doxycycline, amoxicillin, and ceftriaxone. Researchers also described round forms and bacterial aggregates under stressful culture conditions.³

However, a 2025 study by Zhang and colleagues raised an important concern about this model.⁴ The researchers found that B. burgdorferi in stationary-phase laboratory cultures rapidly lost its ability to proliferate. Some cells retained intact membranes but had lost essential chromosomal or plasmid material needed for subsequent growth.

This means that some stationary-phase organisms counted as surviving persisters may instead be damaged, replication-incompetent cells. An organism that appears structurally intact is not necessarily capable of restarting an infection.

The finding does not invalidate all laboratory persister research. It does show that researchers must confirm that surviving organisms retain the ability to recover and reproduce before describing them as viable persisters.

Can Lyme bacteria survive long periods inside ticks?

The same 2025 study found a striking difference between bacteria maintained in culture and bacteria living inside ticks.

B. burgdorferi recovered from ticks after 14 months without a blood meal remained capable of proliferation and showed no evidence of the plasmid loss observed in stationary-phase cultures.⁴

This finding provides clear evidence that the tick environment can support prolonged survival of viable, replication-capable Lyme bacteria. It also suggests that survival may depend on the protected biological environment within the tick rather than solely on an intrinsic bacterial “sleeper cell” program.

Survival inside an unfed tick does not establish that the same process occurs in treated patients. Nevertheless, it confirms that B. burgdorferi can remain viable during prolonged periods of limited nutrients when supported by an appropriate biological environment.

Can Borrelia biofilms tolerate antibiotics?

A 2025 study examined biofilm formation and antibiotic susceptibility in 12 European Lyme disease isolates obtained from erythema migrans biopsies. The isolates included seven strains of Borrelia afzelii and five strains of Borrelia garinii.⁵

All 12 isolates formed biofilms under laboratory conditions. The researchers did not identify conventional antimicrobial-resistance genes. However, the concentrations of antibiotics needed to inhibit biofilm growth were substantially higher than those required for free-living, or planktonic, bacteria. The greatest differences involved doxycycline and ceftriaxone.

These results support phenotypic antibiotic tolerance rather than genetic antibiotic resistance. Bacteria growing within a biofilm may behave differently from individually suspended organisms even when they do not carry resistance genes.

However, this was an in vitro study. It does not establish that clinically significant Borrelia biofilms remain in patients following treatment or that laboratory antibiotic concentrations predict treatment outcomes.

Can bacterial material persist after Lyme bacteria are cleared?

Persistent bacterial material represents a separate mechanism from persistent viable infection.

In 2025, McClune and colleagues demonstrated that polymeric B. burgdorferi peptidoglycan accumulated in mouse liver tissue and remained detectable for weeks.⁶ Kupffer cells and hepatocytes retained the bacterial cell-wall material.

The retained peptidoglycan produced changes in organ-specific and secreted proteins and affected energy metabolism in peripheral blood mononuclear cells. Some of these responses resembled biological findings reported in patients with chronic illness following an acute infection.

This study did not demonstrate living bacteria. Instead, it showed how bacterial material might remain after the infectious organism has been cleared and continue provoking immune or metabolic responses.

Persistent bacterial antigens and persistent viable bacteria are therefore distinct biological possibilities. Finding one does not prove the other.

Can Lyme bacteria hide in protected tissues?

Cabello and colleagues proposed that certain tissues may function as refugia—sites where bacteria could be partially protected from immune responses or antimicrobial activity.²

B. burgdorferi interacts with collagen and other components of the extracellular matrix. The spirochete may also colonize connective tissues with relatively limited blood flow. In these locations, organisms may be less metabolically active and potentially less susceptible to antibiotics that primarily target multiplying bacteria.

This hypothesis offers one possible explanation for experimental persistence. However, the extent to which tissue refugia contribute to persistent illness in treated patients remains unresolved.

Does persistence mean antibiotic resistance?

No. Antibiotic resistance, antibiotic tolerance, persistence, and persistent bacterial antigens describe different phenomena.

Antibiotic resistance generally involves inherited genetic changes that allow bacteria to continue growing despite exposure to an antibiotic.

Antibiotic tolerance allows bacteria to survive temporary exposure without necessarily continuing to grow.

Persister cells are a small antibiotic-tolerant subpopulation that can potentially resume growth when conditions improve.

Persistent bacterial antigens are pieces of an organism that remain after the bacteria are dead or have been cleared.

The available research does not establish conventional genetic antibiotic resistance as the primary explanation for persistent symptoms following Lyme disease treatment. The 2025 biofilm study, for example, found reduced antibiotic susceptibility without identifying conventional resistance genes.⁵

Can Lyme bacteria persist in animals after treatment?

Researchers have reported evidence of B. burgdorferi persistence following antibiotic treatment in some experimentally infected mice and nonhuman primates. Depending on the study, investigators have detected bacterial DNA, RNA, antigens, or organisms with limited biological activity.³

These findings remain challenging to interpret. Detection of bacterial DNA or proteins does not necessarily prove that intact bacteria are alive, capable of replication, or responsible for continuing symptoms.

Nevertheless, animal studies provide sufficient evidence to justify continued research into antimicrobial tolerance and post-treatment persistence. They do not establish how commonly viable bacteria remain in treated people.

What does this research mean for patients?

The newer research does not reduce the persistence question to a simple yes or no answer.

• The tick environment can preserve viable, replication-capable B. burgdorferi for more than a year.
• Some stationary-phase laboratory organisms may be damaged cells that cannot reproduce.
• Biofilm growth can substantially reduce antibiotic susceptibility in vitro without conventional resistance genes.
• B. burgdorferi peptidoglycan can persist after bacterial clearance and produce immune and metabolic effects in mice.
• Animal studies have reported evidence consistent with post-treatment persistence, but their clinical significance remains disputed.

None of these findings independently proves that viable, antimicrobial-tolerant Borrelia routinely persists in patients after appropriate treatment. At the same time, the studies identify biological mechanisms that warrant further investigation rather than dismissal.

Patients may remain ill after treatment for different or overlapping reasons, including ongoing infection, persistent bacterial antigens, tissue injury, immune dysregulation, autonomic dysfunction, co-infections, another illness, or a combination of factors. These possibilities are discussed further in my overview of persistent Lyme disease.

There is currently no routinely available test that can reliably distinguish among all these mechanisms in an individual patient. Treatment decisions therefore require clinical judgment based on the original diagnosis, treatment history, response to therapy, objective findings, symptom pattern, possible co-infections, alternative diagnoses, and risks and benefits of additional treatment.

Frequently Asked Questions

Can Lyme bacteria survive doxycycline?

Laboratory studies have found that some stationary-phase or biofilm-grown Borrelia can survive or require higher concentrations of doxycycline for inhibition. However, some stationary-phase cells may be too damaged to reproduce, and laboratory survival does not prove that doxycycline routinely fails in patients.

Are Lyme persister cells resistant to antibiotics?

Not necessarily. Persister cells are generally phenotypically tolerant rather than genetically resistant. They may temporarily survive antibiotic exposure without acquiring permanent resistance genes.

Do stationary-phase cultures prove Lyme bacteria can remain dormant?

No. A 2025 study found that many stationary-phase B. burgdorferi cells lost essential genetic material and could not resume proliferation. Stationary-phase cultures therefore require careful viability testing before surviving cells can be considered true persisters.

Can Lyme bacteria survive inside ticks for more than a year?

Yes. Researchers recovered viable, replication-capable B. burgdorferi from ticks that had gone 14 months without a blood meal. This demonstrates prolonged survival in the tick environment but does not prove the same survival mechanism occurs in treated patients.

Can parts of Lyme bacteria remain after the infection is cleared?

Yes. A 2025 mouse study found that B. burgdorferi peptidoglycan persisted in liver tissue for weeks and produced systemic biological responses. This represents persistent bacterial material rather than proof of living bacteria.

Do Borrelia biofilms prove that infection persists after treatment?

No. A 2025 laboratory study found that European Borrelia isolates formed biofilms with reduced antibiotic susceptibility. The study supports phenotypic tolerance in vitro but does not establish that clinically significant biofilms persist in treated patients.

Does persistence research prove that ongoing symptoms are caused by active infection?

No. Persistence research identifies plausible biological mechanisms but does not prove that every patient with ongoing symptoms has an active infection. Viable bacteria, retained bacterial antigens, immune responses, tissue injury, co-infections, and other conditions may produce overlapping symptoms.

Clinical Takeaway

Research supports the ability of B. burgdorferi to adapt to environmental stress, tolerate antibiotics under certain laboratory conditions, and survive for prolonged periods in the protected environment of a tick. Animal studies have also reported evidence consistent with post-treatment persistence.

At the same time, newer findings show that some apparent stationary-phase persisters may be replication-incompetent. Other studies demonstrate that nonviable bacterial material can persist and stimulate biological responses without an active infection.

The evidence supports continued investigation into Lyme disease persistence, but viable bacteria, antibiotic-tolerant cells, biofilms, and persistent bacterial antigens should not be treated as interchangeable explanations.

Related Articles

Post-treatment Lyme disease syndrome
Recovery from Lyme disease
How accurate are Lyme disease tests?

References

1. Cabello FC, Godfrey HP, Bugrysheva JV, Newman SA. Sleeper cells: The stringent response and persistence in the Borreliella (Borrelia) burgdorferi enzootic cycle. Environmental Microbiology. 2017;19(10):3846-3862.
2. Cabello FC, Godfrey HP, Newman SA. Hidden in plain sight: Borrelia burgdorferi and the extracellular matrix. Trends in Microbiology. 2007;15(8):350-354.
3. Cabello FC, Embers ME, Newman SA, Godfrey HP. Borreliella burgdorferi antimicrobial-tolerant persistence in Lyme disease and posttreatment Lyme disease syndromes. mBio. 2022;13(3):e03440-21.
4. Zhang J, Takacs CN, McCausland JW, et al. Borrelia burgdorferi loses essential genetic elements and cell proliferative potential during stationary phase in culture but not in the tick vector. Journal of Bacteriology. 2025;207(3):e00457-24.
5. Fabrizio G, Cavallo I, Sivori F, et al. Genomic characterization and antibiotic susceptibility of biofilm-forming Borrelia afzelii and Borrelia garinii from patients with erythema migrans. Frontiers in Cellular and Infection Microbiology. 2025;15:1619660.
6. McClune ME, Ebohon O, Dressler JM, et al. The peptidoglycan of Borrelia burgdorferi can persist in discrete tissues and cause systemic responses consistent with chronic illness. Science Translational Medicine. 2025;17(795):eadr2955.

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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