Combination Antibiotics for Lyme Disease and Tick-Borne Co-Infections

Combination antibiotics were used for Lyme disease and tick-borne co-infections.
Pain and neurological symptoms declined during follow-up.
The observational study cannot prove that treatment caused the improvement.

Can combination antibiotics for Lyme disease and tick-borne co-infections improve persistent symptoms? Xi and colleagues examined treatment outcomes among patients evaluated for Lyme disease and tick-borne co-infections at an infectious disease clinic in Ireland.¹

In their article, A Longitudinal Study of a Large Clinical Cohort of Patients with Lyme Disease and Tick-Borne Co-Infections Treated with Combination Antibiotics, the investigators retrospectively reviewed patients with symptoms attributed to Lyme disease or other tick-borne infections.

Recent reviews have emphasized that tick-borne co-infections can complicate diagnosis and treatment because overlapping symptoms are often nonspecific and standard Lyme disease treatment does not address every possible co-infection. Babesia, for example, is a protozoan infection and requires pathogen-specific treatment rather than the antibiotics typically used for Lyme disease.²

How many patients were included?

The researchers evaluated 301 individuals who were tested for Lyme disease and other tick-borne infections. Of these, 140 patients, or 46.51%, had positive antibody responses to one or more organisms included in the testing panel.

Among these 140 patients:

• 93 patients, or 66.43%, had positive antibody responses to one tick-borne organism
• 47 patients, or 33.57%, had positive antibody responses to multiple organisms

The authors described the latter group as having multiple tick-borne infections. However, the classifications were based primarily on antibody testing. A positive antibody response can indicate previous exposure or an immune response and does not necessarily prove that every organism represented an active infection at the time of treatment.

Which tick-borne organisms were identified?

Among the 140 participants with positive antibody findings:

• 83 patients, or 59.29%, had positive antibody responses to Borrelia alone
• 7 patients, or 5.00%, had positive antibody responses to Rickettsia alone
• 1 patient, or 0.71%, had a positive antibody response to Babesia alone
• 1 patient, or 0.71%, had a positive antibody response to Bartonella alone
• 1 patient, or 0.71%, had a positive antibody response to Ehrlichia alone

The remaining 47 patients had antibody responses involving more than one organism. These combinations included Borrelia, Babesia, Bartonella, Ehrlichia, and Rickettsia.

Co-infections may be clinically important because different pathogens can produce overlapping symptoms yet require different treatments. Antibiotics used for Lyme disease may also cover certain bacterial co-infections, such as anaplasmosis or ehrlichiosis, but they do not treat protozoal infections such as babesiosis or viral tick-borne illnesses.²

Which combination antibiotics were used?

The majority of patients who completed both follow-up visits received a three-antibiotic combination. The most frequently prescribed regimen consisted of:

• Cefuroxime 500 mg
• Rifampicin 300 mg
• Lymecycline 300 mg

The medications were reportedly taken twice daily. Treatment duration ranged from 12 to 40 weeks.

Cefuroxime is an oral cephalosporin used to treat certain manifestations of Lyme disease. Rifampicin has activity against selected bacterial infections, while lymecycline is a tetracycline antibiotic used more commonly in Europe.

Because the three medications were generally administered together, the study cannot determine whether cefuroxime, rifampicin, lymecycline, another component of care, or the combination accounted for the reported changes in symptoms.

The findings therefore relate to combination antibiotic treatment for Lyme disease rather than the effectiveness of any single antibiotic.

What symptoms were most commonly reported?

The three most frequently reported problems were pain, fatigue, and neurological symptoms. Neurological complaints included tingling in the limbs and memory difficulties.

At the first follow-up visit, 118 patients completed symptom assessments. Among them:

• 70 patients, or 59.32%, reported pain
• 57 patients, or 48.31%, reported fatigue
• 48 patients, or 40.68%, reported neurological symptoms

At the second follow-up visit, 101 patients completed symptom assessments. At that time:

• 47 patients, or 46.53%, continued to report fatigue
• 41 patients, or 40.59%, continued to report pain
• 30 patients, or 29.70%, continued to report neurological symptoms

Did pain and neurological symptoms improve?

Between the first and second follow-up visits, the number of patients reporting pain decreased by 41.43%. The number reporting neurological symptoms decreased by 37.50%.

These reductions were statistically significant. The authors reported significant decreases in the incidence of pain and neurological symptoms between the two follow-up visits.

Fatigue decreased by 17.54%, but this change was not statistically significant. Fatigue therefore remained a substantial problem for many patients despite improvement in other reported symptoms.

The investigators also reported improvement in patients’ self-rated health. Median health ratings increased from approximately 3 at the initial visit to 5 at the first follow-up and 6 at the second follow-up.

These findings represent changes reported over time within the treated cohort. Because the study did not include an untreated or placebo comparison group, it cannot establish how much improvement was attributable to antibiotic treatment rather than the natural course of illness, other treatments, changes in care, or additional factors.

How well was combination treatment tolerated?

Of the 101 patients who completed both follow-up visits, 77 reportedly continued to tolerate treatment. Twelve patients required a change in their antibiotic combination because of side effects, and two patients discontinued treatment.

The investigators monitored kidney and liver function during treatment. Patients were also given probiotics because of concerns about gastrointestinal adverse effects and disruption of the intestinal microbiome.

These findings do not mean that prolonged combination antibiotic treatment is appropriate or safe for every patient. Risks depend on the medications prescribed, treatment duration, drug interactions, underlying medical conditions, laboratory findings, and individual tolerance.

Rifampicin, for example, can interact with numerous prescription medications. Combination treatment can also increase the risk of gastrointestinal symptoms, allergic reactions, liver injury, changes in blood counts, antimicrobial resistance, and disruption of the normal microbiome.

How often did patients recall a tick bite or rash?

Only 73 of the 140 participants, or 52.14%, recalled a tick bite.

A bull’s-eye rash was reported by 40 patients, or 28.57%. Sixty-five patients, or 46.43%, reported that they had not developed a bull’s-eye rash, while 31 patients were unsure.

These findings reinforce that the absence of a recalled tick bite or classic rash does not exclude Lyme disease. A tick may be overlooked, and an erythema migrans rash may be absent, unnoticed, uniformly red, or may not have the classic bull’s-eye appearance.

Observational studies can identify clinical associations but cannot determine whether a treatment caused improvement. Laboratory and animal studies provide biologic evidence that may justify future clinical trials, although they cannot establish clinical effectiveness in people.

What have laboratory and animal studies found?

Experimental studies provide a rationale for investigating combination therapy, but they do not establish that these regimens are effective or safe in people.

In a mouse model of persistent Borrelia burgdorferi infection, Alruwaili and colleagues compared individual drugs with several dual- and triple-drug combinations. None of the monotherapies eradicated persistent infection across all detection methods used in the study. Several combinations produced negative results across culture, molecular testing, and xenodiagnostic methods.³

The successful experimental combinations included doxycycline with ceftriaxone, doxycycline with cefotaxime, dapsone with rifampicin, and dapsone with clofazimine. Several three-drug regimens also performed better than monotherapy.

However, these experiments were conducted in mice, not patients. Drug absorption, dosing, immune responses, safety, and treatment outcomes can differ substantially between animals and humans. These findings support additional preclinical and clinical research but should not be interpreted as proof that the same combinations will eradicate persistent infection or improve symptoms in people.

Earlier in-vitro studies also evaluated antibiotic combinations against stationary-phase Borrelia burgdorferi cultures enriched in drug-tolerant cells. Feng and colleagues found that several multi-drug combinations had greater activity than the individual drugs tested alone.⁴

In that in-vitro study, combinations containing dapsone, minocycline, cefuroxime, azithromycin, or rifampin showed activity against stationary-phase organisms. Nevertheless, the most active sulfa-containing combinations remained less effective than a daptomycin, cefuroxime, and doxycycline control combination.

Stationary-phase cultures are laboratory models and do not reproduce the full complexity of human infection. Findings from a test tube cannot determine whether a regimen will be clinically beneficial, tolerable, or safe in patients.

What are the study’s limitations?

The Irish cohort offers useful clinical observations, but several important limitations affect how its findings should be interpreted.

• It was a retrospective observational study rather than a randomized controlled trial.
• There was no untreated or placebo comparison group.
• Most patients received several antibiotics simultaneously.
• Treatment combinations and treatment duration were not uniform.
• Symptoms were assessed with a questionnaire that was not validated specifically for Lyme disease or tick-borne co-infections.
• Not every patient returned for both follow-up visits.
• The analysis compared groups available at different follow-up points rather than reporting a complete controlled outcome for every enrolled patient.
• Positive antibody responses were used to classify patients as having single or multiple tick-borne infections.
• Positive antibodies do not necessarily establish active infection with each organism at the time of treatment.
• Changes in other treatments, supportive care, daily activity, or the natural course of illness may have influenced symptom reporting.

The study also did not compare the three-drug regimen with standard single-antibiotic treatment. It therefore cannot establish that combination therapy was superior to monotherapy or determine whether the reported benefits outweighed the risks of longer treatment.

Symptoms can improve, fluctuate, or worsen over time for reasons unrelated to antibiotic therapy. Without a randomized comparison group, the study cannot prove that combination antibiotics caused the reported improvement.

The results do not establish that cefuroxime, rifampicin, and lymecycline should be routinely prescribed for Lyme disease, persistent symptoms, or presumed co-infections. Additional controlled studies are needed to evaluate which patients might benefit, which organisms are actively present, which combinations should be studied, how long treatment should continue, and how risks should be monitored.

“`html

Frequently Asked Questions

Why are combination antibiotics used for some patients with Lyme disease?

Some clinicians consider combination antibiotics when a patient has suspected or documented tick-borne co-infections, persistent symptoms, treatment intolerance, or a complex clinical presentation. However, the optimal indications, drug combinations, and treatment duration remain uncertain. Treatment decisions should be individualized and should account for the diagnosis, potential co-infections, medication risks, laboratory monitoring, and the patient’s response.

Did this study prove that combination antibiotics caused the improvement?

No. This was a retrospective observational study without a placebo or untreated comparison group. Most patients received cefuroxime, rifampicin, and lymecycline together, making it impossible to determine whether one medication, the full combination, supportive care, the natural course of illness, or other factors accounted for the reported improvements.

Did fatigue improve as much as pain and neurological symptoms?

No. Pain and neurological symptoms declined significantly between follow-up visits. Fatigue decreased to a lesser extent, and the change was not statistically significant. Fatigue remained one of the most commonly reported symptoms at the second follow-up.

Do animal and laboratory studies prove combination treatment works in patients?

No. Mouse and in-vitro studies can identify biological mechanisms and antibiotic combinations that merit further investigation, but they cannot establish clinical effectiveness or safety in people. Controlled human studies are needed before experimental findings can be translated into routine treatment recommendations.

Clinical Takeaway

This observational study found that patients treated with combination antibiotics for Lyme disease and tick-borne co-infections reported reductions in pain and neurological symptoms during follow-up. Fatigue improved less and remained a persistent complaint for many patients.

The findings are clinically important because they describe outcomes in a large cohort treated in a real-world infectious disease practice. Animal and in-vitro studies also provide biologic support for investigating whether certain antibiotic combinations have greater activity than individual drugs.

However, the human study did not include a control group, relied heavily on antibody testing to classify infections, and evaluated several antibiotics administered simultaneously. It therefore cannot establish that the treatment caused the reported improvement, confirm that every suspected co-infection represented active disease, or determine the contribution of any individual medication.

This study supports further investigation of combination antibiotics for Lyme disease and tick-borne co-infections but does not establish that prolonged multi-drug therapy is appropriate for every patient.

Related Articles

Explore additional information on Lyme disease diagnosis, treatment, and common co-infections:

Lyme disease testing
Lyme disease treatment
Bartonella and Lyme disease
Babesia symptoms, diagnosis, and treatment
Persistent Lyme disease overview

References

1. Xi D, Thoma A, Rajput-Ray M, et al. A Longitudinal Study of a Large Clinical Cohort of Patients with Lyme Disease and Tick-Borne Co-Infections Treated with Combination Antibiotics. Microorganisms. 2023;11(9):2152.
2. Popov G, Bashchobanov D, Andonova R. Tick-Borne Co-Infection in Lyme Disease: Clinical Impact, Diagnostic Challenges, and Therapeutic Perspectives. Microorganisms. 2026;14(2):325.
3. Alruwaili Y, Jacobs MB, Hasenkampf NR, et al. Superior Efficacy of Combination Antibiotic Therapy Versus Monotherapy in a Mouse Model of Lyme Disease. Front Microbiol. 2023;14:1293300.
4. Feng J, Zhang S, Shi W, Zhang Y. Activity of Sulfa Drugs and Their Combinations Against Stationary-Phase Borrelia burgdorferi In Vitro. Antibiotics (Basel). 2017;6(1):10.

---

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