Sunday, October 30, 2011

A tale of two more studies: topical antibiotics applied to tick bites to prevent Lyme disease

Feeding Ixodes ticks harboring Borrelia burgdorferi deposit the Lyme disease spirochete in the skin of the victim.  The spirochetes remain in the skin for a few days before entering the bloodstream to spread throughout the host.  The delay in dissemination provides a window of opportunity to stop the infection by simply applying antibiotics to the skin where the tick was feeding.  Topical application of antibiotics would allow patients to avoid experiencing side effects associated with ingesting antibiotics.

ResearchBlogging.orgI recently posted a critique of a study by Knauer and colleagues, who tested the ability of a topical antibiotic to prevent B. burgdorferi infection in lab mice bitten by infected ticks.  As I explained in the post, the antibiotic appeared to prevent infection, but the investigators had used a weakened B. burgdorferi strain to inoculate the mice.  Consequently it wasn't possible to draw any conclusions about the effectiveness of their antibiotic formulation in preventing infection.

Now let's look at two more studies that tested the ability of topical antibiotics to prevent infection in the mouse model of Lyme disease.  These studies were conducted properly with highly infectious B. burgdorferi strains.  One study was published almost 20 years ago.  The other appeared online just last month.  Both studies were published in The Journal of Infectious Diseases.

In their 1993 study Shih and Spielman were able to prevent B. burgdorferi infection by applying at least 1 milligram of tetracycline starting up to two days following the tick bite.  The antibiotic had to be applied twice a day for at least three consecutive days (see table below).  The presence of infection four weeks after tick feeding was assessed by xenodiagnosis, which tests whether the spirochetes could be recovered by ticks placed on the skin at a location distant from the original tick bite.  The investigators also found that penicillin, amoxicillin, ceftriaxone, doxycycline, and erythromycin applied for three days beginning one day after tick feeding prevented infection.

Although this study demonstrated the promise of topical antibiotics in preventing Lyme disease in those who discover a tick feeding on them, a limitation of the study was that most of the antibiotics were dissolved in DMSO, which is not approved for use on humans.  The only antibiotic dissolved in a solvent suitable for humans was erythromycin, which was added into 70% ethanol.

For their 2011 study, Wormser and colleagues decided to dissolve the antibiotics in something else that would be acceptable to apply to human skin.  They rubbed a 2% erythromycin ointment or 3% tetracycline gel over the tick bite 1-2 days after the infected ticks finished feeding on the mice.  The antibiotics were applied twice daily for three days.  Four weeks later urinary bladder and ear tissue were cultured to see whether the mice had a disseminated infection.  The authors found that their antibiotic formulations failed to prevent systemic infection, although erythromycin was able to prevent a persistent infection at the tick bite site in some of the mice (see table below).

Erythromycin and tetracycline were tested in both studies.  Why the stark difference in the effectiveness of the same antibiotics in the two studies?   In the Discussion of their paper, Wormser and colleagues highlighted the major methodological differences between the studies:
  • Different antibiotic concentrations. A much higher concentration of erythromycin was applied to the tick bites in the 1993 study.
  • Different solvents.  DMSO, the solvent used for the 1993 study, may have promoted better penetration of tetracycline into the skin than the ointment and gel formulations selected for the Wormser study.
  • Different placement of infected ticks.  In the 1993 study the infected ticks were placed on the ear for feeding.  In the Wormser study the ticks were placed on the back, where the skin may be thicker and hence more resistant to antibiotic penetration.
  • Different B. burgdorferi strains.  Wormser and colleagues used ticks infected with the highly invasive BL206 strain to inoculate the mice, whereas Shih and Spielman used ticks infected with the less invasive JD1 strain.
  • Different mouse strains.  The C3H mouse strain used in the Wormser study is highly susceptible to dissemination by B. burgdorferi.
For this simple treatment approach to effective, higher concentrations of the antibiotic in a penetrating solvent such as ethanol may be necessary.  Different B. burgdorferi and mouse strains should also be tested in future studies.


Shih, C.-M., & Spielman, A. (1993). Topical prophylaxis for Lyme disease after tick bite in a rodent model Journal of Infectious Diseases, 168 (4), 1042-1045 DOI: 10.1093/infdis/168.4.1042

Wormser, G.P., Daniels, T.J., Bittker, S., Cooper, D., Wang, G., & Pavia, C.S. (2011). Failure of topical antibiotics to prevent disseminated Borrelia burgdorferi infection following a tick bite in C3H/HeJ mice Journal of Infectious Diseases DOI: 10.1093/infdis/jir382
Knauer, J., Krupka, I., Fueldner, C., Lehmann, J., & Straubinger, R.K. (2011). Evaluation of the preventive capacities of a topically applied azithromycin formulation against Lyme borreliosis in a murine model Journal of Antimicrobial Chemotherapy DOI: 10.1093/jac/dkr371

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