Combination Antibiotic Therapy for Treatment of Lyme Disease

0.5 CME. This module discusses differences between antibiotic tolerance and resistance in Lyme disease, demonstrates persistence via tolerance by the Lyme disease spirochete, and evaluates the efficacy of combination therapy versus monotherapy in both animal models and humans.


Monica E. Embers, PhD
Associate Professor in the Division of Immunology
Director of Vector-borne Disease Research
Tulane National Primate Research Center


This module discusses differences between antibiotic tolerance and resistance in Lyme disease, demonstrates persistence via tolerance by the Lyme disease spirochete, and evaluates the efficacy of combination therapy versus monotherapy in both animal models and humans.

Learning objectives

  1. Distinguish antibiotic tolerance from resistance
  2. Examine evidence of persistence via tolerance by the LD spirochete
  3. Describe antibiotic efficacy studies in animal models and their outcomes using combo therapy vs. monotherapy

This session, Combination Antibiotic Therapy for Treatment of Lyme Disease, is approved for 0.5 enduring AAFP Prescribed credits.

AAFP Prescribed credit is accepted by the American Medical Association as equivalent to AMA PRA Category 1 credit(s)™ toward the AMA Physician’s Recognition Award. When applying for the AMA PRA, Prescribed credit earned must be reported as Prescribed, not as Category 1.

The AAFP has reviewed One Health Medical Education for a Changing Climate and deemed it acceptable for AAFP credit. Term of approval is from 01/02/2024 to 01/01/2025. Physicians should claim only the credit commensurate with the extent of their participation in the activity.


Alruwaili, Y., M. B. Jacobs, N. R. Hasenkampf, A. C. Tardo, C. E. McDaniel and M. E. Embers (2023). “Superior efficacy of combination antibiotic therapy versus monotherapy in a mouse model of Lyme disease.” Front Microbiol 14: 1293300.

Ayrapetyan, M., T. Williams and J. D. Oliver (2018). “Relationship between the Viable but Nonculturable State and Antibiotic Persister Cells.” J Bacteriol 200(20).

Barthold, S. W., E. Hodzic, D. M. Imai, S. Feng, X. Yang and B. J. Luft (2010). “Ineffectiveness of tigecycline against persistent Borrelia burgdorferi.” Antimicrobial Agents & Chemotherapy 54(2): 643-651.

Berende, A., H. J. ter Hofstede, A. R. Donders, H. van Middendorp, R. P. Kessels, E. M. Adang, F. J. Vos, A. W. Evers and B. J. Kullberg (2014). “Persistent Lyme Empiric Antibiotic Study Europe (PLEASE)–design of a randomized controlled trial of prolonged antibiotic treatment in patients with persistent symptoms attributed to Lyme borreliosis.” BMC Infect Dis 14: 543.

Cameron, D. J., L. B. Johnson and E. L. Maloney (2014). “Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease.” Expert Rev Anti Infect Ther 12(9): 1103-1135.

Crossland, N. A., X. Alvarez and M. E. Embers (2018). “Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Posttreatment in Rhesus Macaques.” The American Journal of Pathology 188(3): 672-682.

DeLong, A., M. Hsu and H. Kotsoris (2019). “Estimation of cumulative number of post-treatment Lyme disease cases in the US, 2016 and 2020.” BMC Public Health 19(1): 352.

Delong, A. K., B. Blossom, E. L. Maloney and S. E. Phillips (2012). “Antibiotic retreatment of Lyme disease in patients with persistent symptoms: a biostatistical review of randomized, placebo-controlled, clinical trials.” Contemp Clin Trials 33(6): 1132-1142.

Embers, M. E., S. W. Barthold, J. T. Borda, L. Bowers, L. Doyle, E. Hodzic, M. B. Jacobs, N. R. Hasenkampf, D. S. Martin, S. Narasimhan, K. M. Phillippi-Falkenstein, J. E. Purcell, M. S. Ratterree and M. T. Philipp (2012). “Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic Treatment of Disseminated Infection.” PLOS ONE 7(1): e29914.

Fallon, B. A., J. G. Keilp, K. M. Corbera, E. Petkova, C. B. Britton, E. Dwyer, I. Slavov, J. Cheng, J. Dobkin, D. R. Nelson and H. A. Sackeim (2008). “A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy.” Neurology 70(13): 992-1003.

Hodzic, E., S. Feng, K. Holden, K. J. Freet and S. W. Barthold (2008). “Persistence of Borrelia burgdorferi following antibiotic treatment in mice.” Antimicrobial Agents & Chemotherapy 52(5): 1728-1736.

Hunfeld, Klaus-Peter, Eva Ružić-Sabljić, Douglas E. Norris, Peter Kraiczy, and Franc Strle. “Risk of Culture-Confirmed Borrelial Persistence in Patients Treated for Erythema Migrans and Possible Mechanisms of Resistance.” International Journal of Medical Microbiology 296 (2006): 233-41.

Hunfeld, K.-P., E. Ruzic-Sabljic, D. E. Norris, P. Kraiczy and F. Strle (2005). “In Vitro Susceptibility Testing of Borrelia burgdorferi Sensu Lato Isolates Cultured from Patients with Erythema Migrans before and after Antimicrobial Chemotherapy.” Antimicrobial Agents and Chemotherapy 49(4): 1294-1301.

Klempner, M. S., L. T. Hu, J. Evans, C. H. Schmid, G. M. Johnson, R. P. Trevino, D. Norton, L. Levy, D. Wall, J. McCall, M. Kosinski and A. Weinstein (2001). “Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease.” New England Journal of Medicine 345(2): 85-92.

Krupp, L. B., L. G. Hyman, R. Grimson, P. K. Coyle, P. Melville, S. Ahnn, R. Dattwyler and B. Chandler (2003). “Study and treatment of post Lyme disease (STOP-LD).” Neurology 60(12): 1923-1930.

Trouillas, P. and M. Franck (2023). “Complete Remission in Paralytic Late Tick-Borne Neurological Disease Comprising Mixed Involvement of Borrelia, Babesia, Anaplasma, and Bartonella: Use of Long-Term Treatments with Antibiotics and Antiparasitics in a Series of 10 Cases.” Antibiotics (Basel) 12(6).

Wormser, Gary P., Raymond J. Dattwyler, Eugene D. Shapiro, John J. Halperin, A. Steere, Mark S. Klempner, P. Krause, J. Bakken, F. Strle, G. Stanek, L. Bockenstedt, D. Fish, J. Stephen Dumler and Robert B. Nadelman (2006). “The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America.” Clinical Infectious Diseases 43(9): 1089-1134.

Xi, D., A. Thoma, M. Rajput-Ray, A. Madigan, G. Avramovic, K. Garg, L. Gilbert and J. S. Lambert (2023). “A Longitudinal Study of a Large Clinical Cohort of Patients with Lyme Disease and Tick-Borne Co-Infections Treated with Combination

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Course Includes

  • 1 Lesson
  • 2 Quizzes
  • Course Certificate