Pilot study to examine the effect of antibiotic therapy on
MRI outcomes in RRMS
b, * , S.Y. Yao
, C. Stratton
, H. Moses
, P.A. Narayana
, J.S. Wolinsky
Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37212, USA
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
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.
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
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) . Although macrolide
antibiotics are known to possess anti-inflammatory
properties, the anti-inflammatory properties of azithromy-cin
are weak . 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
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.
 Yucesan C, Sriram S. Chlamydia pneumoniae infection of the central
nervous system. Curr Opin Neurol 2001;14:355– 9.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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.
 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:
 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.
 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.
 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.
 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
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
 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.
 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].
 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.
 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.
 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.
 Zalewska-Kaszubska J, Gorska D. Anti-inflammatory capabilities of
macrolides. Pharmacol Res 2001;44:451 –4.
 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.
 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
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