Comments from Wheldon on Flagyl use and Resistance

[Guest guest]

Well, a lovely man who has readily responded to

questions I've asked, once again. Below is my question

and his email response about low dose flagyl use and

resistance likelihood on the Cpn protocal. My response

back is also included.

Jim

> Question re: Flagyl resistance and

intolerance

>

>

>Dr. Wheldon-

>You've kindly answered some questions of mine about

your Cpn protocal

>before, so I hope you will have time to answer some

further ones.

>

>One is about the potential for resistance to flagyo

which could be

>created by the low dose build up that is often

required because of herx

>severity. On a list I correspond on, the following

citations have been

>discussed related to this potential:

>

>http://www.ub.rug.nl/eldoc/dis/medicine/e.j.van.der.wouden/c8.pdf

>

>http://tinyurl.com/62tz2

>

>What constitutes an adequate dose/course of flagyl to

avoid this is, of

>course, another question. Have you had any noticable

resistance build up

>in the cases you consult on?

>

>Secondly is the phenomenon of the " Flagyl wall. " It

is commonly reported

>that some of us seem to reach a sensitization to the

flagyl which is

>more related to the toxicity of the drug-- the side

effects of nausea,

>fatigue, etc-- not the same as the herx reactions.

For example, I was

>had built up to 3 days of flagyl (500mg twice a day)

every week (this

>seemed to work well for me, with steadier improvement

than when I was

>pulsing the flagyl at three week intervals) for

about 5 weeks. No

>problems other than herx during this time. Around

week 6 I had increased

>nausea and debility, and by week 7 I could not

tolerate more than two

>and a half days. When I stopped the symptoms

dissipated over the next

>three days and I could eat again.

>

>I decided to stretch out the flagyl pulses to the 3-4

week intervals you

>recommend to see if this allows less sensitization.

Have you run into

>this problem with patients before? What is your

understanding of the

> " Flagyl wall? "

>

>Thanks for your work,

>Jim Kepner PhD.

>

david.wheldon wrote:

>Jim,

>

>Thanks for your interesting letter.

>

>I've pondered metronidazole resistance in cpn, and

whether it might be

>analoguous to the development of resistance in

Helicobacter.

>

>Metronidazole works by causing single-strain DNA

breaks at the A-T base

>pair, and in sublethal concentrations induces the SOS

'last resort' DNA

>repair pathway which is mutagenic.

>

>But the SOS pathway involves the synthesis of some 15

proteins. If bacterial

>protein synthesis is blocked by bacteriostatic agents

and metronidazole is

>then given, the SOS pathway shouldn't be induced and

the organism shouldn't

>be able to repair the DNA damage; death rather than

mutation should occur.

>

>Analogies may occur with E. coli; strains with a

defective SOS mechanism

>become highly sensitive to metronidazole. E coli in

amino-acid starved

>conditions is also more sensitive. Blocking protein

synthesis with

>rifampicin makes E coli more sensitive to X

radiation, which causes

>double-strand DNA breaks.

>

>So I guess that, under the conditions of treatment,

the emergence of

>metronidazole resistance in cpn is unlikely.

>

>I've not come across the 'Flagyl wall'. It's

certainly not the nicest drug

>to take. There seems to be a lot of idiosyncracy with

it; some people are

>thoroughly nauseated by it; to others it's a breeze.

>

>The Herxheimer effect can be dramatic, and often

seems to go on after the

>metronidazole has been stopped, suggesting that

antigen recognition has at

>last been made, and the body's immune system is now

fully aware of the

>situation. Perhaps macrophages have been purged of

the organism.

>

>Distinct from the Herxheimer effect, one can get

prolonged 'flu-like

>symptoms with altered mental states, rotational

vertigo and peripheral

>neuropathy. This can go on for months and even years.

One might conjecture

>that, as host cell-replacement programmes occur,

bacterial remnants are

>released during host-cell apoptosis and cause

elevated cytokine levels. The

>symptoms are very like those of interferon treatment.

It tends to have a

>diurnal rhythm, which is suggestive of cytokine

activity. The workers at

>Vanderbilt have found elevated porphyrin levels, too.

>

>best wishes,

>

>

>

-

Thanks for your speedy and thoughtful reply. This

helps underscore the importance of the synergistic

effect of the multiple-pathway

antibiotic/bacteriacidal approach. As Stratton said,

" Dead Bugs Don't Mutate, " a statement I have found

captures so succinctly, in such a very American

pragmatic idiomatic way, the whole principle. Your

comments about the longer term cycles are also useful

to try and sort out from all the other herx effects.

I'll pass these comments on to the discussion list

infections/

where it might generate some more observations from

" end users " of the protocal.

Thanks,

Jim

[Guest guest]

Wow, that is some highly fascinating stuff, and new to me and I expect

most of us. Kind thanks to Wheldon and to you.

With some organisms arguably culpable in our illnesses, I would

question whether anti-protein-synth antibiotics do in fact succeed in

fully shutting down their protein synthesis. If they do fully succeed,

the organisms should fail to replicate and should then, as far as I

know, theoretically be progressively cleared by the immune system,

with eventual resolution of allo-immmune inflammation. If I'm not

getting something wrong. This conflicts with the observation that many

with diseases of interest do not become fully well on doxy etc alone

even over years.

So, if the blockade of bacterial protein synthesis by anti-synth drugs

is partial only, I would wonder whether the SOS DNA-repair response

would in fact be blocked or impaired to the desired degree. Alas,

quantification of treatment-relevant phenomena is always difficult, so

one has to take many things into account, and IMO deals with many

shades of unknowns in many places.

I consider my illness to probably be borreliosis, and am currently

doing a similar regimen of doxy (but at 400 mg /d), zith, and, since

last week, tinidazole, at long last. I'm not sure how long I'll stick

- its hard for me to know whats up because I have never herxed on

anything but fluconazole. Despite that, I have improved very robustly

on antimicrobials (tho that could conceivably be coincidence, given

the variability and short duration of my illness prior to this treatment).

<jimk192002@y...> wrote:

> Well, a lovely man who has readily responded to

> questions I've asked, once again. Below is my question

> and his email response about low dose flagyl use and

> resistance likelihood on the Cpn protocal. My response

> back is also included.

> Jim

>

> > Question re: Flagyl resistance and

> intolerance

> >

> >

> >Dr. Wheldon-

> >You've kindly answered some questions of mine about

> your Cpn protocal

> >before, so I hope you will have time to answer some

> further ones.

> >

> >One is about the potential for resistance to flagyo

> which could be

> >created by the low dose build up that is often

> required because of herx

> >severity. On a list I correspond on, the following

> citations have been

> >discussed related to this potential:

> >

> >http://www.ub.rug.nl/eldoc/dis/medicine/e.j.van.der.wouden/c8.pdf

> >

> >http://tinyurl.com/62tz2

> >

> >What constitutes an adequate dose/course of flagyl to

> avoid this is, of

> >course, another question. Have you had any noticable

> resistance build up

> >in the cases you consult on?

> >

> >Secondly is the phenomenon of the " Flagyl wall. " It

> is commonly reported

> >that some of us seem to reach a sensitization to the

> flagyl which is

> >more related to the toxicity of the drug-- the side

> effects of nausea,

> >fatigue, etc-- not the same as the herx reactions.

> For example, I was

> >had built up to 3 days of flagyl (500mg twice a day)

> every week (this

> >seemed to work well for me, with steadier improvement

> than when I was

> >pulsing the flagyl at three week intervals) for

> about 5 weeks. No

> >problems other than herx during this time. Around

> week 6 I had increased

> >nausea and debility, and by week 7 I could not

> tolerate more than two

> >and a half days. When I stopped the symptoms

> dissipated over the next

> >three days and I could eat again.

> >

> >I decided to stretch out the flagyl pulses to the 3-4

> week intervals you

> >recommend to see if this allows less sensitization.

> Have you run into

> >this problem with patients before? What is your

> understanding of the

> > " Flagyl wall? "

> >

> >Thanks for your work,

> >Jim Kepner PhD.

> >

> david.wheldon wrote:

>

> >Jim,

> >

> >Thanks for your interesting letter.

> >

> >I've pondered metronidazole resistance in cpn, and

> whether it might be

> >analoguous to the development of resistance in

> Helicobacter.

> >

> >Metronidazole works by causing single-strain DNA

> breaks at the A-T base

> >pair, and in sublethal concentrations induces the SOS

> 'last resort' DNA

> >repair pathway which is mutagenic.

> >

> >But the SOS pathway involves the synthesis of some 15

> proteins. If bacterial

> >protein synthesis is blocked by bacteriostatic agents

> and metronidazole is

> >then given, the SOS pathway shouldn't be induced and

> the organism shouldn't

> >be able to repair the DNA damage; death rather than

> mutation should occur.

> >

> >Analogies may occur with E. coli; strains with a

> defective SOS mechanism

> >become highly sensitive to metronidazole. E coli in

> amino-acid starved

> >conditions is also more sensitive. Blocking protein

> synthesis with

> >rifampicin makes E coli more sensitive to X

> radiation, which causes

> >double-strand DNA breaks.

> >

> >So I guess that, under the conditions of treatment,

> the emergence of

> >metronidazole resistance in cpn is unlikely.

> >

> >I've not come across the 'Flagyl wall'. It's

> certainly not the nicest drug

> >to take. There seems to be a lot of idiosyncracy with

> it; some people are

> >thoroughly nauseated by it; to others it's a breeze.

> >

> >The Herxheimer effect can be dramatic, and often

> seems to go on after the

> >metronidazole has been stopped, suggesting that

> antigen recognition has at

> >last been made, and the body's immune system is now

> fully aware of the

> >situation. Perhaps macrophages have been purged of

> the organism.

> >

> >Distinct from the Herxheimer effect, one can get

> prolonged 'flu-like

> >symptoms with altered mental states, rotational

> vertigo and peripheral

> >neuropathy. This can go on for months and even years.

> One might conjecture

> >that, as host cell-replacement programmes occur,

> bacterial remnants are

> >released during host-cell apoptosis and cause

> elevated cytokine levels. The

> >symptoms are very like those of interferon treatment.

> It tends to have a

> >diurnal rhythm, which is suggestive of cytokine

> activity. The workers at

> >Vanderbilt have found elevated porphyrin levels, too.

> >

> >best wishes,

> >

> >

> >

>

> -

> Thanks for your speedy and thoughtful reply. This

> helps underscore the importance of the synergistic

> effect of the multiple-pathway

> antibiotic/bacteriacidal approach. As Stratton said,

> " Dead Bugs Don't Mutate, " a statement I have found

> captures so succinctly, in such a very American

> pragmatic idiomatic way, the whole principle. Your

> comments about the longer term cycles are also useful

> to try and sort out from all the other herx effects.

> I'll pass these comments on to the discussion list

> infections/

> where it might generate some more observations from

> " end users " of the protocal.

> Thanks,

> Jim

[Guest guest]

Thanks jim great stuff

> Well, a lovely man who has readily responded to

> questions I've asked, once again. Below is my question

> and his email response about low dose flagyl use and

> resistance likelihood on the Cpn protocal. My response

> back is also included.

> Jim

>

> > Question re: Flagyl resistance and

> intolerance

> >

> >

> >Dr. Wheldon-

> >You've kindly answered some questions of mine about

> your Cpn protocal

> >before, so I hope you will have time to answer some

> further ones.

> >

> >One is about the potential for resistance to flagyo

> which could be

> >created by the low dose build up that is often

> required because of herx

> >severity. On a list I correspond on, the following

> citations have been

> >discussed related to this potential:

> >

> >http://www.ub.rug.nl/eldoc/dis/medicine/e.j.van.der.wouden/c8.pdf

> >

> >http://tinyurl.com/62tz2

> >

> >What constitutes an adequate dose/course of flagyl to

> avoid this is, of

> >course, another question. Have you had any noticable

> resistance build up

> >in the cases you consult on?

> >

> >Secondly is the phenomenon of the " Flagyl wall. " It

> is commonly reported

> >that some of us seem to reach a sensitization to the

> flagyl which is

> >more related to the toxicity of the drug-- the side

> effects of nausea,

> >fatigue, etc-- not the same as the herx reactions.

> For example, I was

> >had built up to 3 days of flagyl (500mg twice a day)

> every week (this

> >seemed to work well for me, with steadier improvement

> than when I was

> >pulsing the flagyl at three week intervals)  for

> about 5 weeks. No

> >problems other than herx during this time. Around

> week 6 I had increased

> >nausea and debility, and by week 7 I could not

> tolerate more than two

> >and a half days. When I stopped the symptoms

> dissipated over the next

> >three days and I could eat again.

> >

> >I decided to stretch out the flagyl pulses to the 3-4

> week intervals you

> >recommend to see if this allows less sensitization.

> Have you run into

> >this problem with patients before? What is your

> understanding of the

> > " Flagyl wall? "

> >

> >Thanks for your work,

> >Jim Kepner PhD.

> >

> david.wheldon wrote:

>

> >Jim,

> >

> >Thanks for your interesting letter.

> >

> >I've pondered metronidazole resistance in cpn, and

> whether it might be

> >analoguous to the development of resistance in

> Helicobacter.

> >

> >Metronidazole works by causing single-strain DNA

> breaks at the A-T base

> >pair, and in sublethal concentrations induces the SOS

> 'last resort' DNA

> >repair pathway which is mutagenic.

> >

> >But the SOS pathway involves the synthesis of some 15

> proteins. If bacterial

> >protein synthesis is blocked by bacteriostatic agents

> and metronidazole is

> >then given, the SOS pathway shouldn't be induced and

> the organism shouldn't

> >be able to repair the DNA damage; death rather than

> mutation should occur.

> >

> >Analogies may occur with E. coli; strains with a

> defective SOS mechanism

> >become highly sensitive to metronidazole. E coli in

> amino-acid starved

> >conditions is also more sensitive. Blocking protein

> synthesis with

> >rifampicin makes E coli more sensitive to X

> radiation, which causes

> >double-strand DNA breaks.

> >

> >So I guess that, under the conditions of treatment,

> the emergence of

> >metronidazole resistance in cpn  is unlikely.

> >

> >I've not come across the 'Flagyl wall'. It's

> certainly not the nicest drug

> >to take. There seems to be a lot of idiosyncracy with

> it; some people are

> >thoroughly nauseated by it; to others it's a breeze.

> >

> >The Herxheimer effect can be dramatic, and often

> seems to go on after the

> >metronidazole has been stopped, suggesting that

> antigen recognition has at

> >last been made, and the body's immune system is now

> fully aware of the

> >situation. Perhaps macrophages have been purged of

> the organism.

> >

> >Distinct from the Herxheimer effect, one can get

> prolonged 'flu-like

> >symptoms with altered mental states, rotational

> vertigo and peripheral

> >neuropathy. This can go on for months and even years.

> One might conjecture

> >that, as host cell-replacement programmes occur,

> bacterial remnants are

> >released during host-cell apoptosis and cause

> elevated cytokine levels. The

> >symptoms are very like those of interferon treatment.

> It tends to have a

> >diurnal rhythm, which is suggestive of cytokine

> activity. The workers at

> >Vanderbilt have found elevated porphyrin levels, too.

> >

> >best wishes,

> >

> >

> >

>

> -

> Thanks for your speedy and thoughtful reply. This

> helps underscore the importance of the synergistic

> effect of the multiple-pathway

> antibiotic/bacteriacidal approach. As Stratton said,

> " Dead Bugs Don't Mutate, " a statement I have found

> captures so succinctly, in such a very American

> pragmatic idiomatic way, the whole principle. Your

> comments about the longer term cycles are also useful

> to try and sort out from all the other herx effects.

> I'll pass these comments on to the discussion list

> infections/

> where it might generate some more observations from

> " end users " of the protocal.

> Thanks,

> Jim

>

>