Drug Combinations against Borrelia burgdorferi Persisters In Vitro : Eradication Achieved by Using Daptomycin , Cefoperazone and Doxycycline
Feng J, Auwaerter PG, Zhang Y. PLoS One. 2015;1–15.
Full text available from http://dx.doi.org/10.1371/journal.pone.0117207
What problem does this address?
Some patients who have been treated for Lyme borreliosis with courses of standard antibiotics such as doxycycline, amoxicillin or ceftriaxone continue to suffer significant debilitating symptoms. The cause remains uncertain but may include the presence of Borrelia persister cells, immune dysfunction or the remains of bacterial debris. Persistence of viable but non-culturable Borrelia has already been demonstrated in mice, dogs and monkeys after antibiotic treatment.
What was studied?
A research team from Johns Hopkins University recently carried out initial in vitro research on Borrelia in a culture medium. They used 27 FDA approved antibiotics and found that certain compounds such as daptomycin, clofazimine and cefoperazone tended to have an effect on Borrelia persister cells. This led on to the current study which compares the effectiveness of combinations of antibiotics, some targeting the actively dividing bacterial cells with some aimed at the persisters in a two pronged approach.
It has been shown that in the lab under conditions of stress Borrelia spirochaetes can form pleomorphic forms. The drugs were tested on a culture of Borrelia which included individual spirochaetes, round bodied forms and micro-colonies of ‘biofilm-like’ aggregates. In a previous lab study the micro-colony persisters were found to be more resistant or tolerant to treatment than free-living or round bodied forms. A special test was used in which dead bacteria showed up red whereas surviving bacteria appeared green.
What did they find?
In this experiment, the antibiotics daptomycin, cefoperazone and doxycycline in a three drug combination was found to be the most effective against more resistant micro-colonies. Other daptomycin combinations had efficacy against persister cells but left some traces of surviving cells behind. The only other non-daptomycin combinations that were effective contained cefoperazone (a cephalosporin marketed as Cefobid).
Why is this important?
Remarkably, given the undoubted financial/healthcare costs and burden of chronic illness following Lyme disease treatment, this is the first proper study looking at how combinations of antibiotics including those active against Borrelia persisters perform in the laboratory. Some of the more effective drugs in this lab experiment are not currently used for treatment of Lyme borreliosis.
The thinking behind the effectiveness of the combination is that doxycycline (inhibits protein synthesis) and cefoperazone (blocks cell wall synthesis) have established activity against Borrelia that is actively growing. Cefoperazone appears to have additional activity against persistent forms as does daptomycin.
The drugs used in this study are not new and have the advantage of already being on national approved drug lists and an established track record for use in humans. Further studies are now needed to see the effects and side-effects of such treatments in live studies with animals and humans before such treatments can be deemed to be safe and effective against Lyme borreliosis and recommended as treatment.
Drugs that are very effective in the lab are not always so effective in humans, so there is a bit of a way to go before we know exactly how much of a breakthrough this is likely to be.