Saturday, March 20, 2010

Tigecycline fails to eradicate persisting Borrelia burgdorferi

Antibiotics are usually successful in treating Lyme disease, especially if administered early.  The problem is that some patients continue to experience symptoms even after completing the recommended treatment regimen.  Although the current IDSA guidelines assert that the lingering symptoms are not due to persisting Borrelia burgdorferi,  the mouse model of Lyme disease clearly demonstrates the survival of live (albeit disabled) spirochetes following treatment with ceftriaxone, one of the antibiotics used to treat disseminated Lyme disease. As I wrote in an earlier post, the key question that must be answered is whether the lingering spirochetes are responsible for the persisting symptoms.  If so, a more potent antibiotic that could eliminate all of the spirochetes (or enough of them to allow the immune system to quickly mop up the rest) would be desired.

The newer antibiotic tigecycline was recently approved for treating skin and intra-abdominal infections caused by complex mixtures of bacteria.  Tigecycline is a tetracycline antibiotic, which blocks translation of mRNA into proteins by sticking tightly to the 30S ribosome subunit of bacteria.  In turns out that tigecycline exhibits greater antimicrobial activity than ceftriaxone (and doxycycline, another Lyme antibiotic) against B. burgdorferi, at least in the test tube.

Barthold and colleagues tested tigecycline to see if it could eradicate B. burgdorferi from persistently infected mice.  Groups of mice infected for 4 months with B. burgdorferi were treated with ceftriaxone (10 mice), a low dose of tigecycline (7 mice), or a high dose of tigecycline (9 mice).  A control group was sham treated with saline.  Three months after treatment was completed, the mice were examined to see if the spirochetes were still in the tissues.  As you might expect, B. burgdorferi DNA was detected by PCR at high levels in multiple tissues in all 10 mice that were administered saline, and the spirochetes were successfully cultured from the tissues.  In the ceftriaxone group, as shown in an earlier study by Barthold's lab, low levels of B. burgdorferi DNA were detected in leg joints from all 10 mice.  Although B. burgdorferi could not be cultured from the ceftriaxone-treated mice, ticks that fed on the mice were able to transmit the spirochetes to immunodeficient (SCID) mice, where B. burgdorferi was detected by PCR at the end of the experiment.  Since transmission requires active penetration of B. burgdorferi through several tissue barriers, the spirochetes that remained following antibiotic treatment must have been alive, although they could not be cultured.  Moreover, several B. burgdorferi mRNA transcripts were detected in some of the ceftriaxone-treated mice, another hint that the spirochetes remained viable (mRNA, unlike DNA, is extremely labile and would quickly degrade in dead bacteria).

How well did tigecycline work?  Despite its heightened potency against B. burgdorferi in test tube experiments and its much longer half-life in mice, tigecycline didn't work any better than ceftriaxone in eliminating the spirochetes, even at the higher dose.

The studies performed by Barthold's group raises several questions:
  • Would prolonging antibiotic treatment eventually eliminate the spirochetes?  Curiously, tigecycline was administered to the mice for only 10 days.
  • Do the spirochetes that remain following antibiotic treatment cause disease?  So far, the answer appears to be, "No."  Unlike the saline-treated mice, the antibiotic-treated mice did not exhibit any signs of disease.  Necropsies failed to reveal a inflammatory response against the spirochetes remaining in the tissues.
  • Do the spirochetes that survive antibiotic treatment give rise to disease later?  The earlier study by Barthold's group showed that although viable, the spirochetes were slowly diminishing in number in the tissues of mice that were treated with antibiotics.  If the mice were followed for a longer period of time, would the disabled spirochetes eventually disappear or revive to elicit a relapse of disease?
  • Is the mouse model even relevant to human Lyme disease?  Borrelia burgdorferi has evolved to persist in the mouse, its natural host, and may act differently in humans.  Obviously the experiments presented here can't be performed on humans, but an animal model that is more relevant to human Lyme disease may be more appropriate for addressing the issues raised by Barthold's work.
Featured paper

Barthold, S.W., Hodzic, E., Imai, D.M., Feng, S., Yang, X., and Luft, B.J. (February 2010).  Ineffectiveness of tigecycline against persistent Borrelia burgdorferiAntimicrobial Agents and Chemotherapy 54(2):643-651.  DOI: 10.1128/AAC.00788-09

Related paper

Hodzic, E., Feng, S., Holden, K., Freet, K.J., and Barthold, S.W. (May 2008).  Persistence of Borrelia burgdorferi following antibiotic treatment in mice.  Antimicrobial Agents and Chemotherapy 52(5):1728-1736.  DOI: 10.1128/AAC.01050-07

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