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Pulsed low-dose antibiotics

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.1 These effects seem to be independent of their antibacterial effect.2

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 transcription3 and greatly reduces the incidence of biofilm persister cells.4 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.

Immunosuppressive effects of high-dose antibiotics

Certain antibiotics are immunosuppressive in dose-dependent fashion. For instance, the tetracycline antibiotics have been widely recognized as being able to inhibit various functions of phagocytes, the white blood cells that engulf and kill bacteria.5 These effects seem to be independent of their antibacterial effect.6

These immunosuppressive properties decrease the amount of L-form and biofilm bacteria killed by the immune system. This is why some people report feeling better on high-dose antibiotics. The high levels of antibiotic prevents the immune system from killing these forms of bacteria, resulting in a temporary decrease in the toxins the pathogens release as they die and the inflammatory cytokines produced by the immune system. However, in reality, the person’s L-form bacteria remain alive and find it easier to spread to new tissues and organs.

A paradox of sorts: minocycline is most effective at lower concentrations. In the hours after taking minocycline, when concentrations of the antibiotic are relatively high, the body is immunosuppressed. Later, when much of the drug is metabolized, the immune system is more active.

Importance of subinhibitory concentrations

The most effective way to avoid suppressing one's immune system is to use low doses of pulsed antibiotics – even at doses below the minimum inhibitory concentration for an antibiotic.

Pulsed dosing refers to administering a dose periodically, such as every 48 hours, rather than once or several times daily. When given in this manner, the immunosuppressive effects of the antibiotics are minimized but their ability to weaken bacterial ribosomes remains intact. Patients gradually increase the dosage of the pulsed antibiotic, so that species of bacteria that are susceptible to all different concentration levels will eventually be targeted.

A bioengineer led team at the University of Washington recently created an antibiotic-containing polymer that releases antibiotic slowly onto the surface of hospital devices, such as catheters and prostheses, to reduce the risk of biofilm-related infections. According to the study's author:

Rather than massively dosing the patient with high levels of released antibiotic, this strategy allows the release of extremely low levels of this very potent antibiotic over long periods of time. We calculated the amount released at the surface that would kill 100% of the bacteria entering the surface zone…. Bacteria that live through antibiotic dosing can go on to produce resistant strains. If 100% of the bacteria approaching the surface are killed, they can’t produce resistant offspring. The classical physician approach, dosing the patient systemically and heavily to rid the patient of persistent bacteria, can lead to those resistant strains. Our approach releases miniscule doses compared to what a physician would use, but releases the antibiotic where it will be optimally effective and least likely to leave antibiotic-resistant survivors.

Buddy Ratner, PhD, Director of the Engineered Biomaterials Program at the University of Washington

Although taken orally, the MP antibiotics are taken in the same manner as those administered by Ratner and team. Because they too are dosed at optimal times in extremely small doses, the chance that long-term antibiotic use might foster resistant bacteria is again, essentially negligible, especially when multiple antibiotics are typically used.

Effectiveness of Marshall Protocol antibiotics when given in pulsed low-dosing

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

  • Clindamycin – A recent study found that clindamycin, an MP antibiotic, is effective at only 1/32 of the minimum inhibitory dose. 8 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, significantly decreased biomass and maximal thickness in both forming and established biofilms.9 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.

N.B. azithromycin is no longer recommended for use while on the MP.

Effectiveness of pulsed low dosing against biofilm formation

Although the mainstream medical community is rapidly acknowledging the large number of diseases and infections caused by biofilms, most researchers are convinced that biofilms are difficult or impossible to destroy, particularly those cells that form the deeper layers of a thick biofilm. Most papers on biofilms state that they are resistant to antibiotics administered in a standard manner. The practice of using pulsed low dosing of antibiotics seems to be particularly effective at targeting biofilm bacteria and is supported by both in vivo and in silico research.

Penetration of biofilm

Some researchers claim that antibiotics cannot penetrate the matrix that surrounds a biofilm. But research by Dr. Kim Lewis of Tulane University and other scientists has confirmed that the inability of antibiotics to penetrate the biofilm matrix is much more of an exception than a rule. According to Lewis, “In most cases involving small antimicrobial molecules, the barrier of the polysaccharide matrix should only postpone the death of cells rather than afford useful protection.”

In a paper entitled “The Riddle of Biofilm Resistance,” 10 Lewis discusses her laboratory-based observations of how pulsed, low dose antibiotics are able to break up biofilm, while antibiotics administered in a standard manner (high, constant doses) cannot. According to Lewis, the use of pulsed, low-dose antibiotics to target biofilm bacteria is supported by observations she and her colleagues have made in the laboratory.

Using computer modeling software, another team of researchers have modeled the action of antibiotics on bacterial biofilms and found that pulsing antibiotics can be a superior way of targeting treatment resistant biofilm bacteria. According to Cogan et al, “Exposing a biofilm to low concentration doses of an antimicrobial agent for longer time is more effective than short time dosing with high antimicrobial agent concentration.” 11

Persisters

After antibiotics penetrate a biofilm, a number of cells called “persisters” are left behind. Persisters are simply cells that are able to survive the first onslaught of antibiotics, and if left unchecked, gradually allow the biofilm to form again. According to Lewis, persister cells form with particular ease in immunocompromised patients because the immune system is unable to help the antibiotic “mop up” all the biofilm cells it has targeted. Paradoxically, dosing an antibiotic in a constant, high-dose manner (in which the antibiotic is always present) helps persisters persevere.12

Conversely, in the case of low, pulsed dosing, the survival of persisters is not enhanced. Pulsed low dosing causes the persister cells to lose their phenotype (their shape and biochemical properties), meaning that they are unable to switch back into biofilm mode. A second application of the antibiotic should then completely eliminate the persister cells, which are still in planktonic or free-floating mode. This method has been characterized by one research team as an example of “resonant activation”:

We proposed a novel strategy to “kill” persister cells by triggering them to switch, in a fast and synchronized way, into normally growing cells that are susceptible to antibiotics.

Fu et al.13

Lewis states: “It is entirely possible that successful cases of antimicrobial therapy of biofilm infections result from a fortuitous optimal cycling [pulsed dosing] of an antibiotic concentration that eliminated first the bulk of the biofilm and then the progeny of the persisters that began to divide.”

Notes and comments

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Antimicrob Agents Chemother. 2000 Dec;44(12):3357-63.

Effect of subinhibitory antibiotic concentrations on polysaccharide intercellular adhesin expression in biofilm-forming Staphylococcus epidermidis.14

Rachid S, Ohlsen K, Witte W, Hacker J, Ziebuhr W. Institut für Molekulare Infektionsbiologie, Röntgenring 11, D-97070 Würzburg, Germany. Abstract Biofilm production is an important step in the pathogenesis of Staphylococcus epidermidis polymer-associated infections and depends on the expression of the icaADBC operon leading to the synthesis of a polysaccharide intercellular adhesin. A chromosomally encoded reporter gene fusion between the ica promoter and the beta-galactosidase gene lacZ from Escherichia coli was constructed and used to investigate the influence of both environmental factors and subinhibitory concentrations of different antibiotics on ica expression in S. epidermidis. It was shown that S. epidermidis biofilm formation is induced by external stress (i.e., high temperature and osmolarity). Subinhibitory concentrations of tetracycline and the semisynthetic streptogramin antibiotic quinupristin-dalfopristin were found to enhance ica expression 9- to 11-fold, whereas penicillin, oxacillin, chloramphenicol, clindamycin, gentamicin, ofloxacin, vancomycin, and teicoplanin had no effect on ica expression. A weak (i.e., 2.5-fold) induction of ica expression was observed for subinhibitory concentrations of erythromycin. The results were confirmed by Northern blot analyses of ica transcription and quantitative analyses of biofilm formation in a colorimetric assay. PMID: 11083640

I think it is not made sufficiently clear on this page why pulsed dosing of small doses of antibiotics would imply that antibiotics resistance development is unlikely.

References

2 , 6 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.
3 Davies J, Spiegelman GB, Yim G The world of subinhibitory antibiotic concentrations. Curr Opin Microbiol. 2006;9:445-53.
4 , 7 , 12 Lewis K Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5:48-56.
9 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.
10 Lewis K Riddle of biofilm resistance. Antimicrob Agents Chemother. 2001;45:999-1007.
11 Cogan NG, Cortez R, Fauci L Modeling physiological resistance in bacterial biofilms. Bull Math Biol. 2005;67:831-53.
13 Fu Y, Zhu M, Xing J Resonant activation: a strategy against bacterial persistence. Phys Biol. 2010;7:16013.
Last modified: 01.19.2014
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