Chapter 8
In keeping with my intention to inform the reader about basic biochemistry and molecular biology, I here provide some concepts about these agents.This section is about agents with antibacterial activity.
Many of these agents are made by organisms such as moulds, and appear to be natural substances which increase the survival of that mould in a soil teeming with other organisms competing for their survival.
One major difference between bacterial and mammalian cells is the presence of a rigid wall external to the cell membrane in the bacterial cells. (Not in protobacteria such as rickettsiae)
This is made of a peptidoglycan and is thicker in gram positive than gram negative organisms.DRUGS WHICH ACT ON BACTERIAL CELL WALLS.
Beta lactam antibiotics (penicillins and cephalosporins) prevent a cross linking reaction called transpeptidation, by the lactam ring forming an irreversible covalent acyl bond with the transpeptidase enzyme. This leads to inhibition of bacterial cell wall synthesis.
Bacitracin, and glycopeptides (vancomycin and teicoplanin) also inhibit cell wall synthesis in different ways.INHIBITORS OF PROTEIN SYNTHESIS.
Tetracyclines interact reversibly with the bacterial 30S ribosomal subunit, blocking the binding of aminoacyl tRNA to the messenger RNA-ribosome complex. The specificity for bacterial and mycoplasmal ribosomes relates to their requirement for active, energy dependent transport into the bacterial cell by a system not found in mammalian cells.
A recent discovery that tetracyclines inhibit metalloproteinases such as collagenases may emerge as another therapeutic avenue in inflammatory states.
Macrolides and ketolides bind to the 50S ribosomal subunit, while lincosamides, aminoglycosides, and mupirocin also work in different ways to inhibit protein synthesis in bacterial cells.
The ketolide, telithromycin may be very useful with resistant organisms.
Rifampicin, metronidazole, and quinolones all inhibit DNA synthesis.
There is major and I would claim, excessive use of antibiotics in animal husbandry.
Because of the difficulty of clearing rickettsiae, I note that Schlunzen and colleagues found that chloramphenicol, clindamycin and the macrolides erythromycin, clarithromycin and roxithromycin bind exclusively to the segments of the 23 S ribosomal RNA at the peptidyl transferase cavity and do not involve any interaction with ribosomal proteins.
Chloramphenicol does block the enzyme activity.
Macrolides do not block the peptidyl transferase activity, even if they bind with the enzyme, but seem to block the tunnel that channels the nascent peptides away from the peptidyl transferase centre.
Research into the exact structure of macrolides reveals mechanisms by which ribosomal resistance develops in these organisms.Macrolides tend to have three structural components: the lactone ring, the desosamine sugar, and the cladinose sugar.
The reactive groups of the desosamine sugar and the lactone ring mediate all the hydrogen bond interactions of erythromycin, clarithromycin and roxithromycin. with the peptidyltransferase cavity.It appears that Mg 2+ ions are important at these binding sites.
The major metabolite, 14 hydroxy clarithromycin is more active than clarithromycin against the spotted fever group of rickettsiae.
The ketolide, telithromycin may be very useful with resistant organisms, as it binds more tightly to ribosomes.
Another macrolide, tylosin, does inhibit peptidyl transferase.
Josamycin has also been used successfully for rickettsial disease.
Rifampicin, metronidazole, and quinolones all inhibit DNA synthesis.Quinolones corrupt activity of two essential enzymes, DNA gyrase and topoisomerase IV in the organisms, inducing them to kill cells by generating high numbers of double strand DNA breaks. Ciprofloxacin is a type I quinolone which works in this way.
I have highlighted these actions with particular reference to intracellular bacteria that have been implacated in CFS.
In regards to rickettsias, Cecile Jadine recommends one week on and three weeks off with these antibiotic courses. It seems to be important to alternate these agents.
The same thing is true for mycoplasma infection.
It is very likely that chronic infection requires more courses because the organism can persist inside cells in a dormant state.
I would consider continuing these courses for many months, and possibly changing from doxycycline to either a macrolide or ciprofloxacin in resistant cases.
Different rickettsias may respond more or less well to particular antibiotic.I do not think there is yet adequate scientific information on this subject.
My most recent recommendation is doxycycline 100mg twice a day for 7 days on then 20 days off repeated for at least 2 cycles.If that does not appear to be successful, I would suggest clarithromycin 500mg bd for 7 days or azithromycin, 500mg once or twice a day for 2 days, wait 5 days, then go back to the doxycycline cycles until the person is better.
Beyond that, ciprofloxacin 750mg twice a day for 5 days or chloramphenicol 500mg 4 times per day are alternatives.
All of these plans should include supplements of lactobacilli of the acidophilus and bifidus group.
Resistance to antibiotics is a crucial aspect in arriving at curative therapies in microbial diseases.
Such resistances may be inherent in certain strains of organisms or may arise through various mechanisms, such as mutation of genes, acquisition of new genes or simply variations of the organism with long quiescent times, when the antimicrobial doesn't kill the dormant organism.
Studies on tetracyclines have revealed resistance in many pathogenic, opportunistic and commensal bacteria.
The genes determining resistance may code for energy dependent efflux of tetracyclines or for a protein which protects bacterial ribosomes from the tetracycline action.
Mobile plasmids or transposons can convey resistance between organisms. (Chopra and Roberts 2001)
As well as antibiotic courses, which are already improving many of my patients, there may be the need to try and mop up some toxic microbial products, or to rectify cytokine patterns.
Epigallocatechin gallate (EGCG) is the major component of green tea extracts and possesses antibacterial, antiviral and antitumour activity.
It can also decrease bacterial resistance to antibiotics.Possibilities for this help include giving infusions of Vitamin C at doses of 10-20Gm per infusion.
Dr Jadin uses supportive therapies as well as antimicrobial agents.
I will expand on all therapies in chapter 9 on therapy.
I strongly believe we should strive to keep gut flora as near normal as possible.
I am disturbed that a number of CFS patients do not appear to tolerate antibiotics well, and some feel very ill while on them.
As well there is documentation that some people are left with irritable bowel like syndromes after antibiotic courses.
This may well be related to longer term changes in colonic flora.
It is claimed by a Dr Ritchie Shoemaker in Pocomoke, Maryland, that cholestyramine at a dose of 9gm 4x per day for 2 weeks can mop up the toxins and lessen symptoms.
The cholestyramine is a resin which can bind and trap molecules such as cholesterol and hepatically excreted toxins in the gut, preventing their reabsorption. This will need careful verification.
I am able to find literature identifying that these resins bind the toxin of clostridium difficile.
In Australia the Questran lite preparation contains aspartame, which I do not support.
This leaves the only other option as colestipol.
At this time I would like more evidence to support this approach.
I will provide some details on anti-viral agents in the chapter on therapy.
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