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 b 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.
The bacterial ribosome
is designated 70S
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 23S location of 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.
Rifampicin inhibits
bacterial DNA polymerase.It is a potent inducer of CYP450 enzymes.
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.
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
minocycline and azithromycin in chronic cases, because of the high intracellulalar
penetration of these antibiotics.
Different rickettsias
may respond more or less well to particular antibiotic.
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.
We can now add the
particular information about TH1 set immune responses as elaborated
by Trevor Marshall.
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 14 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.
