Intermittent therapy, theoretical question

hi all, now, dont think i am getting ahead of myself, this question is purely theoretical for me.

I was thinking, when one gets to the intermittent therapy, from my understanding, you go on a couple of weeks of bacterial static, and then on the last five days, you take flagyli. Finishing both on the same day. With the doxyi & roxyi being taken to stop resistance building against the flagyl.

Now, i was thinking, on the day AFTER the last day, there will still be some flagyl in the system (due to serum half lifes, metabolites etc), and the doxy & roxy will be fading as well. Would this not leave you in a state where the CPni could start to replicate again (ie low bacterial statics), while flagyl is still in your system? and isnt this the situation resistance may build under?

I am no doctor, it would just seem "safer" to stop the flagyl a day or something earlier than the bacterial statics? again, just a theoretical question for me, as i wont be onto intermittent therapy for some time yet.

Oh, its YOU again!  The main aim of taking doxycycline and roxithromycin together is to stop yourself developing resistance by just taking one of the two for long periods, then stopping it and starting again, or taking piddling little doses of it.  It is quite hard to develop resistance to flagyli  I have been on intermittent therapy now for two years, and apart from the first time, I stopped everything dead on the same day and have had no problems.  Indeed, I am still improving now, slowly.  I might not be able to produce anything as spectacular as your chart, but I was one hell of a lot worse than you to start off with.  I can stand on one leg, though, without falling over........Sarah 

 

Started the Wheldon regime in August 2003, due to very aggressive SPMSi.  Moved to intermittent therapy after one year.  In May 2006 still take this, two weeks every two months.  EDSSi was about 7, now less than 2.

An Itinerary in Light and Shadow  Berger.

Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

Gosh it is not my understanding that in intermittant therapy the doxyi/roxyi is to stop resistence, it is to force any possible EBi's into the "stuck" half RB state which is anerobic so that they are, in that state, vulnerable to flagyl which works on anaerobic bacteria. The different life forms of CPn have different vulnerablities so you want to make sure you are gtting them in the right phase.
marie
On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.
"Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

Well, duh!  I admit I only read the part about intermittent therapy once, months ago, but I had thought it was two weeks of abxi with flagyli thrown in in the middle, like on days four through nine.  Must go back and study the protocol.  Must go back and study the protocol.  (Repeat after me...)  I swear, every time I read it again, I learn something new, even when David HASN'T changed it in a while...

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems.  Mohandas Gandhi

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

I remembered reading something about this on David's site.   He says:

"The eventual aim is to give all three agents intermittently so that there is some respite from antibiotics. This, the final leg of treatment, may entail a 14 day course of doxycycline and roxithromycin, with a five day course of metronidazole in the middle. This course is given once a month. After several months the intervals between the antibiotics may be cautiously extended. Rifampicin is not suitable for intermittent use, and azithromycin may be given instead."

So what you say about the bacteriostatic abxi going on for a few days after stopping the bacteriocide is what David recommends.

Michele:  on Wheldon protocol since 1st May 2006 for a variety of long standing ailments, also spokesperson for Ella started Wheldon protocol 17th March 2006 for RRMSi

Sussex, UK

Michèle (UK) GFAi: Wheldon CAPi 1st May 2006. Daily Doxyi, Azi MWF, metroi pulse.

Honestly, men!  I just went through to ask DW why he had changed this without telling me.  (I didn't take my mallet.)  His reply was, after looking: "Oh yes, I did, didn't I, but it doesn't matter whether you take it in the middle or at the end."  So, yes, MacK and Michele you are both right, but I haven't been giving incorrect information.  In any case, my reasoning above still stands.......Sarah 

 

Started the Wheldon regime in August 2003, due to very aggressive SPMSi.  Moved to intermittent therapy after one year.  In May 2006 still take this, two weeks every two months.  EDSSi was about 7, now less than 2.

An Itinerary in Light and Shadow  Berger.

Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.
By the way, to prove that it doesn't matter whether you take it in the middle or at the end, as I have always done, the text at the moment says one thing, whereas the diagram says the other.  I think it is time for dinner and a Fellini film.......Sarah
Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

I really don't know more than anyone else (the learning curve being steep for everyone) but, considering everything, it might be for the best for metronidazole to be given towards the end of the two weeks' combined protein-synthesis inhibitors, stopping it just short of the end of that two weeks. That way you allow the maximum time to push the remaining bacteria into the cryptic phase and allow a day or two for the metronidazole to leave the system. Whether this is important I doubt; bacterial numbers should be very few by that time and they'll be in the cryptic phase. Opportunities for bacterial escape are slender; were any fresh EBs to be made they would be opened by NACi. As EBs do not reproduce they should not be able to mutate and so the emergence of resistance to NAC is most improbable.

D W - [Myalgia and hypertensioni (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazole. No medication now. Morning BP typically 110/75]
 I have done already two two-week pulses of Doxyi and Roxi with Tinii during the last 5 days. My logic was the same as yours, David. By the way, no Lipitor  since the last pulse. LDNi only. Doing great. Like Sarah, I am under the impression that I am still improving.

Cured of multiple sclerosisi, stopped the Wheldon's protocol in Nov,2008. Use only LDNi.

Sarah, yes I noticed the difference between the diagram and the test, but then I'm very sure about David's verbal skill, but maybe his computer diagram making skills are not up to the same standard, so I think I will go with the words, when the time comes.   We will just have to suck it and see. 

I just love these little dometics... mallet or no mallet.   I'm sure if Hamish had domestics on line they would not be as funny...He thinks I don't have a sense of humour, I think it is just different to his... 

Michele:  on Wheldon protocol since 1st May 2006 for a variety of long standing ailments, also spokesperson for Ella started Wheldon protocol 17th March 2006 for RRMSi

Sussex, UK

Michèle (UK) GFAi: Wheldon CAPi 1st May 2006. Daily Doxyi, Azi MWF, metroi pulse.

Sarah, Perhaps this IS a Fellini film.

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems.  Mohandas Gandhi

The difference between what we do and what we are capable of doing would suffice to solve most of the world’s problems. Mohandas Gandhi

As EBs do not reproduce they should not be able to mutate and so the emergence of resistance to NACi is most improbable.

However, if we are assuming NAC is being used completely by itself during certain periods (I dont know whether we are assuming that?)...

...then it seems like any spontaneous NAC-resistant mutant that might develop during RB fission in the persister reservoir and become liberated as an EB during those certain periods, should also be capable of undergoing EB-->RB conversion and reproducing during those same periods. Assuming it has enough time to accomplish all this within said period.

This of course is only one consideration and others may also apply here. 

I think we are talking about NACi all by itself for the times between the pulses for long term therapy to destroy the disulphide bonds of the EBi's and keep future CPn contact in the population from resulting in a rising EB load and future reinfection. Eric , my understanding is that the cysteine rich shell of the EB's is what makes them both capable of transforming to RB's as soon as in the cytoplasm of the cell (they have to be able to transform quickly once in or die)and this also causes it to be vulnerable to NAC. My GUESS is that the possibility of resistance to NAC is slim. you know one thing that is interesting about the CPn research is that it has never demonstrated a resistance to an antibitic yet, though below MIC is of course a stimulant to morph into another safer form (crypitc, RB back to EB etc). It seems' it's bag of tricks is to be able to change forms. not to resist in the traditional way. IMHOi it might be that it's flexibility in life forms and enduring tough EB's have been obtained at the evolutionary cost of lack of flexibility in altering it's reproductive pathways, thus inability to resist.
I hope so anyway
marie

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.
"Color out side the lines!"

On CAPi since Sept '05 for MSi, RAi, Asthmai, sciatica. EDSSi at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxyi 200, Azith 3x week, Tinii cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithro

Eric, I've no practical experience of this, but I would have thought that any potentially NACi resistant mutant would be in a catch 22 situation. Either it would not be able to make the tough 'geodesic' EBi coat, or, were it able to do this, then it would be doomed to be an unopened EB forever, as the breaking of a superficial disulphide bond (one intended to be opened) is likely a family property of simple thiols.

Michele, Are you detracting from my skills as an artist? When I was a student and a junior doctor I did cartoons of many of my teachers - all in a kindly way, and often gave them copies. I only have two left; one is of John Tobin, Director of the Public Health Laboratory, and his wife: they are in a rowing boat on the river Thames (or Isis) ignoring the sign on the bank which says 'Danger: Weir'. The other is of David Oppenheimer, of Oppenheimer's Neuropathology fame. It's dated 1978. Link: here . H'mm. . . actually, on re-examining this cartoon, I have to admit that you may be in the right on this. A six stringed violin. . . without a bridge. . . and f-holes displaced to the upper bouts of the belly! Seriously, I must make alterations to keep that page consistent.

D W - [Myalgia and hypertensioni (typically 155/95.) Began (2003) taking doxycycline and macrolide and later adding metronidazole. No medication now. Morning BP typically 110/75]

Oh God/Godess... David, is there nothing you can't do.   Great cartoon, I must admit I would not have noticed the anatomical deficiencies of the violin unless you had pointed them out.   Maybe its the computer skills that are falling behind the others.

Michele:  on Wheldon protocol since 1st May 2006 for a variety of long standing ailments, also spokesperson for Ella started Wheldon protocol 17th March 2006 for RRMSi

Sussex, UK

Michèle (UK) GFAi: Wheldon CAPi 1st May 2006. Daily Doxyi, Azi MWF, metroi pulse.

It looks maybe more like a medieval vielle. Oppenheimer needs a lesson on how to hold his bow and where on the fiddle to place it. I have often had to tell students to keep their elbows down, but this beats any of them!

- Kate D 

I meant to say that the overall impression the drawing gives is terrific, actually, which is what counts in art! 

DW as artist Long retired boss of the PHLS at Oxford and his wife by DW when a junior doctor

 

Michele and Kate, just to show that we two are still talking, here is the other one, of the Thames incident.  I photographed it just now.........Sarah 

 

Started the Wheldon regime in August 2003, due to very aggressive SPMSi.  Moved to intermittent therapy after one year.  In May 2006 still take this, two weeks every two months.  EDSSi was about 7, now less than 2.

An Itinerary in Light and Shadow  Berger.

Completed Stratton/Wheldon regime for aggressive secondary progressive MSi in June 2007, after four years, three of which intermittent.   Still improving bit by bit and no relapses since finishing treatment.

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