Science behind Marshall Protocol antibiotics

Science behind Marshall Protocol antibiotics

The Marshall ProtocolA curative medical treatment for chronic inflammatory disease. Based on the Marshall Pathogenesis. (MP) employs rotating combinations of bacteriostatic antibiotics at pulsed low dosesAdministration of an antibiotic periodically such as every 48 hours and in amounts small enough that the immunosuppressive effects of the antibiotics are minimized. for maximum effectiveness. The type of bacterial pathogens the MP targets are chronic forms, bacteria that grow much more slowly than acute forms.

Safety of Marshall Protocol antibiotics

Main article: Safety of Marshall Protocol antibiotics

For some physicians, the long-term use of the Marshall Protocol (MP) antibiotics inspires concern about bacterial resistance. However, the MP includes several measures to minimize, if not entirely eliminate, any chance that bacteria could become resistant to long-term use of antibiotics:

carefully selected antibiotics, one of which is minocycline, an antibiotic which has been in use for over 40 years yet continues to be effective against MRSA¹ and to reduce disease severity even after follow-up several years later²
pulsed-low dosing of antibiotics – often below the minimum inhibitory concentrationThe lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation. Dosing at well below the MIC improves the MP's effectiveness against slow-growing chronic pathogens and reduces the likelihood of resistance. – so as not to create “persister cells” or suppress the production of the body's natural antibiotics, the antimicrobial peptidesBody’s naturally produced broad-spectrum antibacterials which target pathogens.
varying combinations of antibiotics reduce the likelihood that a bacterium could develop resistance by subverting the use of a given antibiotic
regular dosing of olmesartan (Benicar)Medication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor., a medication which is a Vitamin D Receptor agonistA substance such as olmesartan (Benicar) or 1,25-D which activates the Vitamin D Receptor and transcribes the genes necessary for a proper innate immune response. and is effective in activating the immune system against antibiotic-resistant diseases

The evidence that the MP is not creating resistant communities of bacteria comes in low levels of co-infections such as Candida among the MP cohort as well as the unmistakable immunopathological reactionA temporary increase in disease symptoms experiences by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed., which cannot be explained through any other way except as an indication of bacterial die-off.

Pulsed low-dosing of Marshall Protocol antibiotics

Main article: Pulsed low-dose antibiotics

Antibiotics are typically dosed at levels above the minimum inhibitory concentration (MIC) so as to reduce the likelihood of bacterial resistance. While the MIC may be relevant for acute infections, dosing at that level can still suppress the immune response and aid the growth of chronic infections including those implicated in chronic inflammatory disease. For instance, some antibiotics, when administered at high dosages, have been widely recognized as being able to inhibit various functions of phagocytes.³ These effects seem to be independent of their antibacterial effect.⁴

The Marshall Protocol uses subinhibitory dosage levels of antibiotics. Dosing at well below the MIC improves the MP's effectiveness against chronic pathogens and further reduces the likelihood of bacterial resistance. Pulsed dosing greatly reduces the incidence of biofilm persister cells.⁵ The presence of a sustained immunopathological response is evidence that the MP uses antibiotics in such a way that it does not suppress the immune system.

Bactericidal vs. bacteriostatic antibiotics

As a whole, the antibiotics employed by the Marshall Protocol have a primarily bacteriostatic as opposed to a bactericidal action. Bactericidal antibiotics kill the bacteria causing the infection through direct action, usually by causing the cells to split open, or lyse. Bacteriostatic antibiotics act on the internal workings of the bacterial cell to stop it dividing, decreasing the production of bacterial exoproteins, and so slow down the advance of the infection.

Generally speaking, bacteriostatic antibiotics place the burden for clearing an infection on an active immune response.

Studies have shown that the MP's bacteriostatic antibiotics - all but one of the MP antibiotics are bacteriostatic - are effective when given in pulsed low doses. Several studies have shown that even when administered in low, pulsed doses, the bacteriostatic antibiotics are still able to decrease the production of bacterial exoproteins.⁶

Clindamycin – A recent study found that clindamycin, an MP antibiotic, is effective at only 1/32 of the minimum inhibitory dose. ⁷ According to the study's authors, this very low dose resulted in enhanced uptake of the bacteria by polymorphonuclear cells and enhanced killing of the pathogens by phagocytes, both kinds of white blood cells.
Azithromycin – Researchers at the University of Iowa found that subinhibitory (extremely low dose) concentrations of azithromycin, an MP antibiotic, significantly decreased biomass and maximal thickness in both forming and established biofilms.⁸ These concentrations of azithromycin inhibited biofilms in all but the most highly resistant isolates. In contrast, subinhibitory concentrations of gentamicin, which is not a bacteriostatic antibiotic, had no effect on biofilm formation. In fact, biofilms actually became resistant to gentamicin at concentrations far above the minimum inhibitory concentration.

Mechanisms of action

Name	Action(s)
Minocycline	interferes with bacterial protein synthesis by binding to the 30S subunit of the bacterial ribosome; may bind the PXR Nuclear Receptor; inhibits activity of caspase-3
Azithromycin (Zithromax)	interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome
Clindamycin	interferes with bacterial protein synthesis by binding to the 50S subunit of the bacterial ribosome
Demeclocycline (Declomycin)	interferes with bacterial protein synthesis by binding to the 30S and 50S subunit of the bacterial ribosome
Bactrim DSSulfa antibiotic used by patients on the Marshall Protocol. Combination of sulfamethoxazole and trimethoprim. Works by blocking bacterial folic acid synthesis.	inhibits dihydropteroate synthase, an enzyme that allows bacteria to use folic acid

Inhibition of bacterial ribosome activity (minocycline, azithromycin, clindamycin, demeclocycline)

All the MP antibiotics except BactrimSulfa antibiotic used by patients on the Marshall Protocol. Combination of sulfamethoxazole and trimethoprim. are bacteriostatic. Bacteriostatic antibiotics are a class of antibiotics that work by disabling bacterial ribosomes – small, dense, structures that allow the pathogens to replicate and survive. When an antibiotics binds to a bacterial ribosome, it limits the growth of bacteria by interfering with bacterial protein production, DNA replication, or other aspects of bacterial cellular metabolism.

Folate reductase inhibition (Bactrim DS)

Bactrim DS works by interfering with the ability of bacteria to create and replicate their DNA. Bactrim DS inhibits dihydropteroate synthase, an enzyme that allows bacteria to use folic acid. Since folic acid is an essential precursor in the synthesis of several of the base pairs needed to create DNA, inhibition of the enzyme will stop the pathogen from creating the genetic material it needs to survive.

Activation of Pregnane X Nuclear Receptor (minocycline)

The affinity (Kd) of minocyclineBacteriostatic antibiotic used by Marshall Protocol patients. for the bacteria's 30S ribosome is not as high as one might otherwise expect based on its action. For this reason, it seems likely that minocycline may affect immune function in other ways. One possibility is the Pregnane X Nuclear Receptor (PXR).

A recent paper has suggested that various tetracycline antibiotics including clindamycinBacteriostatic antibiotic used by patients on the Marshall Protocol. activate the PXR.⁹ Whether that conclusion is confirmed by further research remains to be seen.

The conclusion of that paper is somewhat at odds with the in silicoExperiment technique performed on computer or via computer emulation. model produced by Trevor Marshall, PhD, from which he has concluded that of the tetracyclines, minocycline is the only one that activates the PXR.

If this were true, the activation of the PXR by minocycline would confirm patient reports that suggest that taking extra minocycline provides symptom relief. When active, the PXR transcribes CYP3A4, which breaks down 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol., a vitamin D metabolite which interferes with the activity of the body's other nuclear receptorsIntracellular receptor proteins that bind to hydrophobic signal molecules (such as steroid and thyroid hormones) or intracellular metabolites and are thus activated to bind to specific DNA sequences which affect transcription..

Minocycline acting as a PXR agonist may be responsible for the palliation achieved when using high-dose minocycline, a treatment advocated by the Road Back Foundation.

Inhibition of caspase-3 (minocycline)

Caspase-3 is a protease, which breaks apart the VDRThe Vitamin D Receptor. A nuclear receptor located throughout the body that plays a key role in the innate immune response. receptor structure and thus limits the ability of VDR to do gene transcription. Minocycline is known to inhibit Caspase-3 activation.¹⁰¹¹

Read more: Antibiotics, Science behind Protocol

References

¹⁾ Pan A, Lorenzotti S, Zoncada A Registered and investigational drugs for the treatment of methicillin-resistant Staphylococcus aureus infection. Recent Pat Antiinfect Drug Discov. 2008;3:10-33.

²⁾ O'Dell JR, Paulsen G, Haire CE, Blakely K, Palmer W, Wees S, Eckhoff PJ, Klassen LW, Churchill M, Doud D, Weaver A, Moore GF Treatment of early seropositive rheumatoid arthritis with minocycline: four-year followup of a double-blind, placebo-controlled trial. Arthritis Rheum. 1999;42:1691-5.

³⁾ Labro MT Interference of antibacterial agents with phagocyte functions: immunomodulation or "immuno-fairy tales"? Clin Microbiol Rev. 2000;13:615-50.

⁴⁾ Golub LM, Ciancio S, Ramamamurthy NS, Leung M, McNamara TF Low-dose doxycycline therapy: effect on gingival and crevicular fluid collagenase activity in humans. J Periodontal Res. 1990;25:321-30.

⁵⁾ , ⁶⁾ Lewis K Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5:48-56.

⁷⁾ Milatović D Effect of subinhibitory antibiotic concentrations on the phagocytosis of Staphylococcus aureus. Eur J Clin Microbiol. 1982;1:97-101.

⁸⁾ Starner TD, Shrout JD, Parsek MR, Appelbaum PC, Kim G Subinhibitory concentrations of azithromycin decrease nontypeable Haemophilus influenzae biofilm formation and Diminish established biofilms. Antimicrob Agents Chemother. 2008;52:137-45.

⁹⁾ Yasuda K, Ranade A, Venkataramanan R, Strom S, Chupka J, Ekins S, Schuetz E, Bachmann K A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine. Drug Metab Dispos. 2008;36:1689-97.

¹⁰⁾ Chang CJ, Cherng CH, Liou WS, Liao CL Minocycline partially inhibits caspase-3 activation and photoreceptor degeneration after photic injury. Ophthalmic Res. 2005;37:202-13.

¹¹⁾ Festoff BW, Ameenuddin S, Arnold PM, Wong A, Santacruz KS, Citron BA Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury. J Neurochem. 2006;97:1314-26.

Last modified: 06.28.2010