Using a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages

Commentary: There are many potential mechanisms to explain persistence of borrelia after standard antibiotic therapies, including gene recombination, where borrelia can modify its surface antigen VlsE, and non-expressed vls, in gene cassettes, creating different outer surface antigens, helping to avoid immune recognition (Variable VlsE Is Critical for Host Reinfection by the Lyme Disease Spirochete. Rogovskyy AS, et al. PLoS ONE 8(4): e61226. http://dx.doi.org/10.1371/journal.pone.0061226) as well as recent studies that have identified a number of genes and pathways that shed light on the mechanisms of persister formation or survival. Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics but can re grow leading to post-treatment relapse. Examples include TB, syphilis, endocarditis, brucellosis, and biofilm infections (including Lyme disease). Mechanisms of persistence also include toxin–antitoxin molecules, DNA repair or protection, phosphate metabolism, anti-oxidative defense and macromolecule degradation (Persisters, persistent infections and the Yin–Yang model, Ying Zhang; Emerging Microbes and Infections (2014) 3, e3; doi:10.1038/emi.2014.3). We also have the problem of borrelia changing form between cell wall and cystic forms (cell wall deficient forms) and going into the intracellular compartments, where certain antibiotics may not penetrate well, with known treatment failures due to persistence of borrelia sequestering in antibiotically privileged sites. This includes the skin/fibroblasts (Klempner), eye (Preac-Mursic, Meier), ligamentous tissue (Haupl), joints (Priem, Bradley, Fitzpatrick), CNS (Coyle, Leigner), endothelial cells and macrophages (Ma et al, Infect Immun 1991 Feb;59(2):671-8; Malawista SE et al, J Immunol 1993 Feb 1;150(3):909-15) as well as biofilms (Sapi, McDonald). Novel approaches to eliminating persister cells are therefore necessary if we are to find a more effective treatment for Lyme disease. In this article recently published in PLoS one biology, researchers hypothesize that sequential antibiotic treatments with frequent rotations and fluctuating environments may help to reduce resistant bacterial populations. H. pylori is one example where sequential treatments have been effective. We have used combination therapies and sequential treatments in our clinic for years, combined with addressing the 16 points on MSIDS map, and find this approach to be useful (but not necessarily curative), where the majority of patients improve. Some of the newer drug regimens identified by Dr Ying Zhang from John Hopkins University may also have greater efficacy in combination and in sequential treatments (Feng J, Auwaerter PG, Zhang Y (2015) Drug Combinations against Borrelia burgdorferi Persisters In Vitro: Eradication Achieved by Using Daptomycin, Cefoperazone and Doxycycline. PLoS ONE 10(3): e0117207. doi:10.1371/journal.pone.0117207). Further studies of antibiotic rotations and sequential treatments need to be performed in Lyme patients with persistent symptoms to identify more effective therapies.

Using a Sequential Regimen to Eliminate Bacteria at Sublethal Antibiotic Dosages, PLOS | Biology