The Marshall Protocol (MP) employs rotating combinations of subinhibitory bacteriostatic antibiotics at pulsed doses for maximum effectiveness. The type of bacterial pathogens the MP targets are chronic forms, bacteria that grow much more slowly than acute forms.
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:
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 reaction, which cannot be explained through any other way except as an indication of bacterial die-off.
Antibiotics are typically dosed at levels below the minimum inhibitory concentration (MIC) so as to reduce the likelihood of bacterial resistance. While the MIC may be relevant for acute infections, such dosing can suppress the immune response towards chronic pathogens and aid their growth. For instance, some antibiotics, when administered at levels above the MIC inhibit phagocyte function.3 These effects seem to be independent of their antibacterial effect.4
Thus, dosing at levels below the MIC improves the Marshall Protocol's effectiveness against chronic pathogens and further reduces the likelihood of bacterial resistance. At the same time, pulsed dosing modulates microbial transcription5 and greatly reduces the incidence of biofilm persister cells.6 The presence of a sustained immunopathological response is evidence that the MP uses antibiotics in such a way that it enhances the antibacterial properties of the drugs while minimizing their immunosuppressive effects.
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.7
Emerging research now suggests that antibiotics have much broader range of actions that once supposed.
| 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; significantly inhibited expression of co-stimulatory molecules (CD40 and CD86) and major histocompatibility complex (MHC) class II by dendritic cells; reduces toll-like receptor 4 expression, interleukin-12 production and the allostimulatory capacity of dendritic cells10 |
| 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 DS | inhibits dihydropteroate synthase, an enzyme that allows bacteria to use folic acid |
All the MP antibiotics except Bactrim 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 antibiotic 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.
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.
The affinity (Kd) of minocycline 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 clindamycin activate the PXR.11 Whether that conclusion is confirmed by further research remains to be seen.
The conclusion of that paper is somewhat at odds with the in silico 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-D, a vitamin D metabolite which interferes with the activity of the body's other nuclear receptors.
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.
Caspase-3 is a protease, which breaks apart the VDR receptor structure and thus limits the ability of VDR to do gene transcription. Minocycline is known to inhibit Caspase-3 activation.1213