E. Hodzic, S. Feng, K. Holden, K.J. Freet, and S.W. Barthold. (2008). Persistence of Borrelia burgdorferi following antibiotic treatment in mice. Infection and Immunity 52(5):1728-1736.
Controversy surrounds the management of those Lyme disease patients who continue to experience symptoms following treatment with the recommended course of antibiotics. These persisting symptoms, which include fatigue, sleep disturbances, and concentration difficulties, can be debilitating. The central question that underlies the controversy is whether the symptoms result from Borrelia spirochetes that survive treatment. If so, further treatment with oral or intravenous antibiotics, sometimes lasting for many months or even years, may be warranted, as Lyme disease advocates insist. However, the standard treatment guidelines do not recommend antibiotic treatment regimens lasting longer than one month. Supporters of the guidelines contend that post-treatment symptoms are not due to active Borrelia infection and that further treatment with antibiotics are not supported by clinical studies. Critics of the guidelines disagree with the interpretation of the clinical studies and cite cell culture and animal studies that suggest survival of Borrelia following antibiotic treatment. Insurance companies cite the guidelines in refusing to pay for costly long-term antibiotic treatment.
Early in 2008, Hodzic and colleagues at UC Davis published a study that examined the fate of Borrelia burgdorferi in infected mice treated for one month with ceftriaxone, an antibiotic commonly used to treat Lyme disease. The investigators succeeded in visualizing spirochetes in the tissues of a few mice. A typical example is presented in the image below (Figure 1 of the Hodzic et al. paper). Panel B shows a tissue section of a joint from a mouse that was treated with ceftriaxone initiated 4 months following infection with B. burgdorferi. The tissue was examined one month after antibiotic treatment was completed. Immunohistochemical staining clearly revealed a solitary spirochete (arrow). Panel A shows a joint from an infected mouse that was sham treated with saline. As expected, spirochetes were observed in tissues from most of the control mice, with up to four appearing in a section.
One could argue that the spirochetes observed in the ceftriaxone-treated mice were simply dead microbial carcasses awaiting removal. This interpretation appeared to be supported by the marked decrease in B. burgdorferi DNA copy number in mice tissues with time, as measured by quantitative PCR. However, ticks that fed on these mice were able to acquire and transmit the spirochetes to uninfected SCID mice, indicating that the spirochetes remained infectious despite ceftriaxone treatment. Yet all attempts to culture the bacteria from the treated mice, the ticks that fed on the mice, and even the SCID mice that the ticks fed on failed, even though B. burgdorferi was detected in the mouse tissues and ticks by PCR. In contrast, B. burgdorferi was successfully cultured from all control (saline treated) mice and the ticks that fed on the mice. These results suggest that B. burgdorferi that remained in treated mice were alive and infectious (and transmissible) but were impaired in their ability to replicate.
The most important question for those suffering from post-treatment symptoms is whether the spirochetes that survive antibiotic treatment cause clinical symptoms; the infectiousness of the spirochetes is less relevant. The authors microscopically examined the joints and hearts of the SCID mice for signs of inflammation. SCID mice are especially susceptible to developing severe inflammation when infected with B. burgdorferi. Nevertheless, inflammation was not detected in the SCID mice that acquired the disabled (yet infectious) spirochetes from ticks that previously fed on antibiotic-treated mice. This result does not rule out the possibility that disabled spirochetes contribute to post-treatment symptoms in humans by a microscopically undetectable mechanism. If residual spirochetes do indeed elicit clinical symptoms, then elimination of the spirochetes would be desired. Additional treatment with ceftriaxone may not be the best choice since it targets the cell walls of actively replicating bacteria. The mouse model developed by the UC Davis group will allow the investigators to test different treatment approaches for elimination of these persisting spirochetes.