Metronidazole for Multidrug Resistant Tuberculosis:

1
Metronidazole for Multi-drug Resistant
Tuberculosis a Quantitative Evaluation of its
Effectiveness
In Kwon Park, MD1 Clifton Barry, PhD2
1Department of Medicine, Georgetown University
Hospital, Washington, DC 2Tuberculosis Research
Section of NIAID, NIH, Bethesda, MD
Georgetown University
Abstract
Results
NIH and the National Tuberculosis Hospital in
South Korea are currently collaborating in a
ongoing clinical trial, where the effectiveness
of metronidazole against multi-drug resistant
(MDR) tuberculosis (TB) is investigated. In this
study, 60 Korean patients with known pulmonary
MDR TB are randomized to either the treatment arm
(standard regimen metronidazole) or placebo arm
(standard reg. placebo). PET/CT of the chest
is performed on each patient at the entry to the
study and after 8 weeks of treatment. The goal
of this project is to invent an algorithm where
the pre-and post-treatment PET/CT images are
quantitatively analyzed (rather than
qualitatively by radiologists). Using an image
processing software, the 3D volume in the
thoracic cavity corresponding to the Hounsfield
Units of -1000 to -100 on the CT images is
delineated as the Region of Interest (ROI). This
ROI is then applied to the corresponding PET
images. The volume of the lung tissue with a
certain range of PET intensity values is
calculated and plotted against the corresponding
PET intensity values. This plot is generated for
both pre- and post-treatment on each patient and
displayed simultaneously. When used in
conjunction with the qualitative analysis by
radiologists and clinical monitoring, this
algorithm will be a valuable tool in evaluating
the effectiveness of metronidazole against MDR TB.
Introduction
TB remains to be a significant threat to the
mankind. Although the incidence of TB is
decreasing in the developed countries, it is
sharply increasing in the resource poor
countries. Also, the emergence of multi-drug
resistant (MDR) and extensively drug resistant
(XDR) TB warrants an urgent need for more
effective anti-TB drug regimen. Recent studies
have shown that the anaerobic adaptation of
mycobacterium tuberculosis (MTB) likely plays a
significant role in its disease process. Induced
by oxygen deprived environments, MTB goes into
non-replicating persistent state (1, 2). At this
anaerobic state, it has been shown that MTB is
resistant to isoniazid and sensitive to
metronidazole (3). NIH and the National
Tuberculosis Hospital in South Korea are
currently conducting a randomized clinical trial
to investigate the effectiveness of metronidazole
against MDR TB, testing the hypothesis that
metronidazole would be highly active in killing
anaerobic sub-population of MTB in human TB. The
study also aims to use PET/CT scans as a
quantitative measure in monitoring TB
chemotherapy.
Figure 2 Volume of the lung tissue vs. the
corresponding PET intensity values for Patient 1
(top) and Patient 2 (bottom), Pre- and
Post-treatment plots. Because of the double
blindness of the study, which experimental group
(metronidazole or placebo) the above patients
belonged to will not be known until the clinical
trial is ended.
Methods
60 patients who are admitted to the National TB
Hospital in Korea with known pulmonary MDR TB are
randomized and double blinded to either the
treatment arm (standard regimen metronidazole)
or placebo arm (standard reg. placebo). PET/CT
of the chest is performed on each patient at the
entry to the study and after 8 weeks of
treatment. Using AMIDE (an open source image
processing software available in the Internet),
the PET/CT images from the first two patients who
have finished the 8 week course of treatment have
been analyzed using the following algorithm.
First, the 3D volume in the thoracic cavity
corresponding to the Hounsfield Units of -1000 to
-100 on the CT images was delineated as the
Region of Interest (ROI). In this way, only the
lung tissue was included in the analysis,
excluding other structures in the thoracic cavity
such as the heart and the bones. Also, this
method removed any subjectivity that could be
introduced by the analyst in delineating the lung
tissue from the surrounding structures. The 3D
ROI was then applied to the PET images. The
volume of the lung tissue with a certain range of
PET intensity values was calculated and plotted
against the corresponding PET intensity values.
This plot was generated for both pre- and
post-treatment on each patient and displayed
simultaneously for visual comparison.
Conclusion
When used in conjunction with the qualitative
analysis by radiologists and conventional
clinical monitoring such as time to clearing the
sputum, the analysis method introduced above will
provide additional objectivity in evaluating the
effectiveness of metronidazole against MDR TB in
the above clinical trial.
References

• Wayne, LG. (1994). Dormancy of mycobacterium
  tuberculosis and latency of disease. Eur J Clin
  Microbiol Infect Dis 13(11) 908-14.
• Wayne LG, H. L. (1996). An in vitro model for
  sequential study of shiftdown of mycobacterium
  tuberculosis through two stages of nonreplicating
  persistence. Infect Immun 64 2062-9.
• Wayne LG, S. H. (1994). Metronidazole is
  bactericidal to dormant cells of mycobacterium
  tuberculosis. Antimicrob Agents Chemother 38
  2054-8.

Figure 1 CT and PET scan images from Patient 1.