Vanderbilt Article in Press

A forum for the discussion of antibiotics as a potential therapy for MS

Vanderbilt Article in Press

Postby SarahLonglands » Tue Jun 14, 2005 4:45 am

Pilot study to examine the effect of antibiotic therapy on
MRI outcomes in RRMS


S. Sriram
b, * , S.Y. Yao
b
, C. Stratton
a
, H. Moses
b
, P.A. Narayana
c
, J.S. Wolinsky
c
a
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
b
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
c
Neurology University of Texas Health Science Center at Houston, Houston, TX, USA

Received 1 November 2004; received in revised form 18 February 2005; accepted 14 March 2005

Abstract

This trial examined the safety and possible MRI and clinical effects of anti-chlamydial antibiotic therapy in relapsing –remitting MS
(RRMS). Newly diagnosed MS patients were selected to participate if they showed Chlamydia pneumoniae gene in their CSF and had one or
more enhancing lesions on brain magnetic resonance imaging (MRI). After a 4-month run in phase of monthly MRI, patients were
randomized to receive rifampin (300 mg twice daily) and azithromycin (500 mg every other day) for 6 months or placebo (PBO). Patients
then had monthly MRI on therapy and two additional scans on months 12 and 14. Lumbar punctures were repeated between months 7 and 8
and within 2 weeks of termination of the study. Data on 4 patients on treatment and 4 on PBO were available for analysis. The primary
outcome measure of showing a beneficial effect on enhancing lesions was not met. However, there was a significant difference in brain
parenchymal fraction loss favoring those patient receiving antibiotics compared with PBO ( p
_
0.02). Three of the four patients on antibiotic
therapy cleared the organism from the CSF by month 12; in the PBO group one patient cleared the organism. The reduction in atrophy in
patients receiving antibiotics must be viewed with caution, due to the small number of patients studied.
D 2005 Elsevier B.V. All rights reserved.


4. Discussion
The primaryoutcome measureofthe number of
enhancing lesions was not significantly altered with anti-biotic
therapy. However, a delayed reduction in volume of
enhancing lesions was seen in a post hoc analysis in three of
four patients on antibiotics. Moreover, anti-chlamydial
therapy may have stabilized brain atrophy over a 14-month
period in this small number of patients with RRMS.
Treatment was safe and well tolerated over 6 months. There
was no difference in the clinical outcomes of EDSS and
relapse rate.
In spite of the small number, we believe that these
preliminary study suggests unexpected stabilization in
brain atrophy. These results mirrors the results of a study
done with RRMS and scheduled pulsed intravenous
methylprednisolone (IVMP) [19]. Although macrolide
antibiotics are known to possess anti-inflammatory
properties, the anti-inflammatory properties of azithromy-cin
are weak [20]. Azithromycin, unlike roxithromycin
does not impair the cytokine response to lipopolysacchar-ide
and did not decrease joint swelling in carrageen
induced paw edema in rats [21,22]. Anti-infective therapy
likely impacts brain atrophy through a different process
than IVMP and its mechanism remains unexplained.
Larger studies will be needed to confirm this treatment
effect. Given the difficulties in performing double blind
placebo controlled studies, we would suggest that a larger
trial is feasible as a combination therapy with existing
therapies.

Acknowledgements
This study was funded by a grant from the National MS
society and a K23 award to HM from the NIH. We thank the
members of DSMB, the MS clinic staff, Dr. John West, Paul
Griffin, John Falker and Stephen Smith for their support in
the conduct of the study.

References
[1] Yucesan C, Sriram S. Chlamydia pneumoniae infection of the central
nervous system. Curr Opin Neurol 2001;14:355– 9.
[2] Sriram S, Stratton CW, Yao S, Tharp A, Ding L, Bannan JD, et al. C.
pneumoniae infection of the CNS in MS. Ann Neurol 1999;46:6– 14.
[3] Buljevac D, Flach HZ, Hop WC, Hijdra D, Laman JD, Savelkoul HF,
et al. Prospective study on the relationship between infections and
multiple sclerosis exacerbations. Brain 2002;125:952– 60.
[4] Munger KL, Peeling RW, Hernan MA, Chasan-Taber L, Olek MJ,
Hankinson SE, et al. Infection with Chlamydia pneumoniae and risk
of multiple sclerosis. Epidemiology 2003;14:141– 7.
[5] Boman J, Roblin PM, Sundstrom P, Sandstrom M, Hammerschlag
MR. Failure to detect Chlamydia pneumoniae in the central nervous
system of patients with MS. Neurology 2000;54:265.
[6] Gieffers J, Pohl D, Treib J, Dittmann R, Stephan C, Klotz K, et al.
Presence of Chlamydia pneumoniae DNA in the cerebral spinal fluid
is a common phenomenon in a variety of neurological diseases and not
restricted to multiple sclerosis. Ann Neurol 2001;49:585– 9.
[7] Ikejima H, Haranaga S, Takemura H, Kamo T, Takahashi Y, Friedman
H, et al. PCR-based method for isolation and detection of Chlamydia
pneumoniae DNA in cerebrospinal fluids. Clin Diagn Lab Immunol
2001;8:499 – 502.
[8] Layh-Schmitt G, Bendl C, Hildt U, Dong-Si T, Ju¨ttler E, Schnitzler P,
et al. Evidence for infection with Chlamydia pneumoniae in a
subgroup of patients with multiple sclerosis. Ann Neurol 2000;
47:652 – 5.
[9] Marcos MA, Sanz A, Vidal J, Graus F, Jimenez MT. Lack of detection
of C. pneumoniae in CSF of patients with MS. Presented as an
Abstract at the International Chlamydia Meeting, Helsinki; 2000.
[10] Sotgiu S, Piana A, Pugliatti M, Sotgiu A, Deiana GA, Sgaramella E,
et al. Chlamydia pneumoniae in the cerebrospinal fluid of patients
with multiple sclerosis and neurological controls. Mult Scler 2001;7:
371–4.
[11] Sriram S, Yi-Yao S, Stratton CS, Calabresi P, Ikejima H, Yamamoto Y.
Comparative study of the presence of C. pneumoniae in the CSF of
patients with clinically definite and monosymptomatic MS. CDLI.
Clin Diag Lab Immunol 2002;9:1332– 7.
[12] Zuzak KB, Theodore M, Wager E, Myers L, Gaydos CA. Lack of
detection of C. pneumoniae by PCR and tissue controls in CSF of MS
patients and controls. Presented at the International Chlamydia
Meeting at Helsinki; 2000.
[13] Hao Q, Miyashita N, Matsui M, Wang HY, Matsushima T, Saida T.
Chlamydia pneumoniae infection associated with enhanced MRI
spinal lesions in multiple sclerosis. Mult Scler 2002;8:436 – 40.
[14] Yamamoto Y. PCR in the diagnosis of infection: detection of bacteria
in CSF. Clin Diagn Lab Immunol 2002;9:508 – 14.
0 1 2 3 4 5 6 7 8 9 10 1112 131415
-2
-1
0
1
2
Placebo Antibiotic
Month
Z score
Worse
Better
Fig. 3. Z4 values of the placebo and antibiotic treated groups throughout the
study. Positive values represent a worsening of MRI measures of disease
activity and negative values represent improvement.
S. Sriram et al. / Journal of the Neurological Sciences xx (2005) xxx – xxx 4
[15] Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers
GC, et al. New diagnostic criteria for multiple sclerosis: guidelines for
research protocols. Ann Neurol 1983;13:227– 31.
[16] Wolinsky JS, Narayana PA, Noseworthy JH, Lublin FD, Whitaker JN,
Linde A, et al. Linomide in relapsing and secondary progressive MS:
Part II: MRI results. MRI Analysis Center of the University of Texas-Houston,
Health Science Center, and the North American Linomide
Investigators. Neurology 2000;54:1734– 41 [see comments].
[17] Bedell BJ, Narayana PA, Wolinsky JS. A dual approach for
minimizing false lesion classifications on magnetic resonance images.
Magn Reson Med 1997;37:94– 102.
[18] Wolinsky JS, Narayana PA, Johnson KP. United States open-label
glatiramer acetate extension trial for relapsing multiple sclerosis: MRI
and clinical correlates. Multiple Sclerosis Study Group and the MRI
Analysis Center. Mult Scler 2001;7:33 –41.
[19] Zivadinov R, Rudick RA, De Masi R, Nasuelli D, Ukmar M, Pozzi-Mucelli
RS, et al. Effects of IV methylprednisolone on brain atrophy
in relapsing – remitting MS. Neurology 2001;57:1239–47.
[20] Zalewska-Kaszubska J, Gorska D. Anti-inflammatory capabilities of
macrolides. Pharmacol Res 2001;44:451 –4.
[21] Ianaro A, Ialenti A, Maffia P, Sautebin L, Rombola L, Carnuccio R,
et al. Anti-inflammatory activity of macrolide antibiotics. J Pharma-col
Exp Ther 2000;292:156 – 63.
[22] Scaglione F, Rossoni G. Comparative anti-inflammatory effects of
roxithromycin, azithromycin and clarithromycin. J Antimicrob Che-mother
1998;41(Suppl. B):47 – 50.
S. Sriram et al. / Journal of the Neurological Sciences xx (2005) xxx – xxx 5
Last edited by SarahLonglands on Tue Jun 14, 2005 12:40 pm, edited 2 times in total.
SarahLonglands
Family Elder
 
Posts: 2105
Joined: Thu Jun 17, 2004 3:00 pm
Location: Bedfordshire UK

Postby bromley » Tue Jun 14, 2005 6:17 am

Sarah,

This is fairly detailed stuff but the results look pretty dissappointing. None of the patients appear to have seen the improvements that you have reported e.g. your MRIs showed a reduction of lesions. Could this be because they were not following Dr Wheldon's anti-biotics regime?


Bromley
User avatar
bromley
Family Elder
 
Posts: 1887
Joined: Fri Sep 10, 2004 3:00 pm

Postby SarahLonglands » Tue Jun 14, 2005 6:46 am

Bromley,

No, I think the main difference is the lack of metronidizole in the regime. What they were taking apart from this should be equally effective, although I do know that Stratton would love to be able to use roxithromycin. David started with the Vanderbilt regime then altered it because he has always preferred to use doxycycline over minocycline and had the availability of roxithromycin.

Also they were all people with early RRMS disease, so won't have had the same lesion load. My disease was also very active at the time. It seems silly to say, but I could almost feel it grinding to a halt. So it isn't really surprising that they didn't show my lesion reduction. This is the trouble with trials: to start off with, it takes so long to start because they have to find the people who fit the predefined criteria, then they are only allowed a certain amount of time to show results, then, in this case, at least one of the people involved would dearly loved to have been able to use flagyl (metronidizole) but this was not allowed. Remember, criteria are not set solely by the people actually doing the trial.

Now, the big test will be in August, when I have my two year scan. Eek!! :o

Sarah
SarahLonglands
Family Elder
 
Posts: 2105
Joined: Thu Jun 17, 2004 3:00 pm
Location: Bedfordshire UK

Statistics

Postby gibbledygook » Tue Jun 14, 2005 7:06 am

Somewhere in the article it states that there is a decrease in lesion volume in three out of the four patients on the antibiotics. Here it is:

There was no statistical difference in either the number
or the volume of the enhancing lesions noted when
comparing the three different epochs (pre-treatment, on
treatment and post treatment); the primary outcome
measure of the study was not met. Three of four patients
who received antibiotics showed a decrease in the volume
of enhancing lesions,
while in the fourth patient in whom
there was no decrease, scans at months 12 and 14 were not
done. Two of four patients in the placebo arm showed an
increase in volume, threefold over that seen during the run
in phase (Fig. 1).

The decrease was not apparently statistically significant. I have noticed that in a trial of the antiviral medication, valacyclovir a reduced lesion formation was also notied but this was also considered not statistically significant. Well sod that! Any reduction strikes me as a pretty good outcome!! :lol:
User avatar
gibbledygook
Family Elder
 
Posts: 1412
Joined: Mon Feb 14, 2005 4:00 pm
Location: London

Wrong thread

Postby SarahLonglands » Tue Jun 14, 2005 7:14 am

I must have pressed the wrong button somewhere, because I meant it to be added to Daunted's list of papers! Sorry. :(

But as Gibbledygook said, "Sod that!" ( referring to lesion load reduction)
SarahLonglands
Family Elder
 
Posts: 2105
Joined: Thu Jun 17, 2004 3:00 pm
Location: Bedfordshire UK

Re: Wrong thread

Postby Daunted » Tue Jun 14, 2005 8:21 am

Just a caveat from a graduate student who knows a little bit about statistics:

With a trial this small, the chances of getting statistical significance are slim, even IF the treatment is tremendously effective. In is an "underpowered" trial

(see http://www.cceb.upenn.edu/cert/Materials/numbers.html )
On Vanderbilt Antibiotic Protocol since January
User avatar
Daunted
Family Elder
 
Posts: 271
Joined: Sun May 30, 2004 3:00 pm
Location: University Town, USA

Postby SarahLonglands » Tue Jun 14, 2005 11:32 am

rifampin (300 mg twice daily) and azithromycin (500 mg every other day) for 6 months


What I should also have said earlier is that neither of these two drugs is remotely immunomodulatory and were chosen for the trial for this reason. It does mention this in the Discussion section:

Azithromycin, unlike roxithromycin
does not impair the cytokine response to lipopolysacchar-ide
and did not decrease joint swelling in carrageen
induced paw edema in rats [21,22]


Daunted's comments about statistics are quite correct, but the team faced enormous difficulties finding a larger number of people having just the right specifications demanded for the trial: length of time since diagnosis, size and amount of lesions and so on.

Sarah
.
SarahLonglands
Family Elder
 
Posts: 2105
Joined: Thu Jun 17, 2004 3:00 pm
Location: Bedfordshire UK

Postby Daunted » Tue Jun 14, 2005 2:30 pm

Yes, Sarah, I think it is important that people realize that this trial was essentially done to make a point- that any improvement was solely due to elimination of CPn.

There's no reason to use this protocol, otherwise. In fact, this protocol is quite expensive and quite uncomfortable as compared to the Wheldon regimen, or the most recent one from Dr. Stratton, Minocycline/Zithromax/Flagyl.
On Vanderbilt Antibiotic Protocol since January
User avatar
Daunted
Family Elder
 
Posts: 271
Joined: Sun May 30, 2004 3:00 pm
Location: University Town, USA

Recent Vanderbilt Study- more info and why

Postby Jimk » Sat Jun 18, 2005 12:46 pm

I had an email correspondance with David Wheldon, lovely man by the way, about this study. Sent him a copy of the abstract and turns out he had already been sent the full study by Stratton. This particular study was specifically to demonstrate that reduction of Cpn effected lesions by using abx which are not antiinflammatory in nature. David said that Flagyl was not used in this study because it is not recognized as an anti-chlamydial drug (this remains for other studies). Flagyl's effect on the cryptic form of Cpn is one of the unique contributions of Stratton, et al's work... see the patent materials. David also noted:
"There is a great deal in the full-text article which is not covered in the
abstract. For instance, although there was no shrinkage of enhancing lesionsduring the period of study, post-study MRIs did show lesion shrinkage in this group.

The study was meticulous, even to the point of giving the placebo group
riboflavin to give the urine the same colouration as rifampicin."


I'm being treated using Wheldon's regime for Cpn, although I don't have MS. I have followed the discussion on on these forums because it is the only place I've found that is looking at the Stratton/Wheldon treatments and research. I hope my comments are helpful and welcome here.
Jim
User avatar
Jimk
Family Member
 
Posts: 69
Joined: Fri Jun 17, 2005 3:00 pm
Location: Ohio, USA

Postby SarahLonglands » Sat Jun 18, 2005 2:39 pm

Hello Jim,

Yes, they certainly are! Welcome on board.

Sarah ( David Wheldon's other half!) :wink:
SarahLonglands
Family Elder
 
Posts: 2105
Joined: Thu Jun 17, 2004 3:00 pm
Location: Bedfordshire UK

Postby Arron » Wed Jun 22, 2005 12:36 pm

Jim, you, your thoughts and your experiences are absolutely welcome here. This is a community of independent thinkers committed to the act of knowledge sharing. Welcome!
Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk.
User avatar
Arron
Volunteer Moderator
 
Posts: 892
Joined: Sun Feb 01, 2004 4:00 pm
Location: California, USA

Re: Recent Vanderbilt Study- more info and why

Postby Daunted » Wed Jun 22, 2005 12:58 pm

Jimk,

Do you mind telling us why you are doing the regimen? I am not diagnosed with MS, I have an odd fibromyalgia-like MS-like Chronic-fatigue-like unremitting syndrome that is slowly evolving.

I'm quite proud to part of this board, with Sarah and the others, as I think this is an excellent source of information!

I have something to add for everyone, straight from my good doctor:

Vitamin C drives C.pneumoniae into inclusion body (cryptic) phase (Azenabor AA, Chaudhry AU.,Chlamydia pneumoniae survival in macrophages is regulated by free Ca2+ dependent reactive nitrogen and oxygen species., J Infect. 2003 Feb;46(2):120-8.)

This article suggests that doses of Vitamin C knock CPn into cryptic mode, so taking lots of Vitamin C may be beneficial.

Endotoxin can also deplete Vitamin C considerably (Pleiner J,et.al, Inflammation-induced vasoconstrictor hyporeactivity is caused by oxidative stress., J Am Coll Cardiol. 2003 Nov 5;42(9):1663-5.)

So now I've added Vitamin C 1 Gram 3x a day. You have to titrate up due to GI issues but I seem to tolerate this quite well now.

Just something cheap and easy to add!

D.
On Vanderbilt Antibiotic Protocol since January
User avatar
Daunted
Family Elder
 
Posts: 271
Joined: Sun May 30, 2004 3:00 pm
Location: University Town, USA

Reply to Daunted

Postby Jimk » Wed Jun 22, 2005 6:21 pm

I've had CFS/FMS/MCS for about 20 years: pain, fatigue, inflammation, brain fog, cystitus, etc, etc.. I started at a new CFS/FMS Clinic last August which, amongst other things, tests for a big panel of occult infections (viral and bacterial). Cpn came up high on the antigen tests. They treat with tetracycline, which I did for three months. Huge herx (severe pain in every part of my body, utter fatigue, irritabillity, discoordination, etc,) for the first week, which then tapered, but the only major improvement was in lessening in overall pain.

I then started researching and found David Wheldon's regime and Stratton's work, and ran David's protocal and reasoning past my CFS doc who was quite willing to prescribe the whole thing. This was in December 2004. The switch to doxycycline was no problem. The addition of zithro gave another round of herx, so it was apparent it was killing more and deeper in tissues not reached by the doxy. It wasn't until I added the Flagyl that I felt a lifting of some deeper fatigue, as if a weight I was dragging was lightened. I was only able to tolerate a couple of days of Flagyl at a time as it makes me quite nauseated and ill-feeling- separate from it's Cpn kill effects. I recently switched to Tinidazole which I tolerate much better, and can do the full 5 day pulses.

I would say my improvement is steady and gradual. I recently added no-flush niacin, on re-reading Stratton's patent materials, which seems to add a kick to the abx, and had added buffered vitamin C at my doc's suggestion to counter neurotoxin reactions-- I appreciate your post about it's stringent effect on the Cpn!

Interestingly, this is the only Forum I have found with a specific discussion of Cpn and chronic disease, despite it's link to Chronic Fatigue and Fibro. I think the MS community is much more ahead on this, thanks to David Wheldon and to the Vanderbilt group.
User avatar
Jimk
Family Member
 
Posts: 69
Joined: Fri Jun 17, 2005 3:00 pm
Location: Ohio, USA

Testing

Postby Brainteaser » Wed Jun 22, 2005 8:09 pm

Dear Jim,

Possibly getting away from the subject a little, but I note you say you managed to achieve a wide range of viral and bacterial testing. Would this be through simple pathology tests that a doctor could prescribe or was it something special, associated with the clinic you went to?

Regards & thanks,
Phil.
User avatar
Brainteaser
Family Elder
 
Posts: 435
Joined: Fri Jan 14, 2005 4:00 pm
Location: Melbourne, Australia

Re: Reply to Daunted

Postby Daunted » Wed Jun 22, 2005 9:59 pm

Jim,

How much Niacin are you taking; is it as Niacinamide? I don't recall the exact role of Niacin.
On Vanderbilt Antibiotic Protocol since January
User avatar
Daunted
Family Elder
 
Posts: 271
Joined: Sun May 30, 2004 3:00 pm
Location: University Town, USA

Next

Return to Antibiotics

 


  • Related topics
    Replies
    Views
    Last post

Who is online

Users browsing this forum: No registered users


Contact us | Terms of Service