JAC Advance Access published online on July 29, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg345
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Medical
Microbiology, University College London, Royal Free Campus, Rowland
Hill Street, London NW3 2PF, UK
* Corresponding author. E-mail: stepheng{at}rfc.ucl.ac.uk.
Received 20 September 2002
; revised 17 April 2003
; accepted 29 May 2003
A model for evaluating the potency of a new anti-tuberculosis
drug or a drug combination, based on a decline in the number of
viable tubercle bacilli in patient's sputum during 5 days
mono-therapy has been reported. One popular measure is based on
the analysis of the decline in bacterial counts during the first
48 h of therapy and has been called early bactericidal activity
(EBA). Such analyses could detect EBA for only a few drugs and were
subject to variations in results obtained in different sites. To
address these problems we applied a reiterative exponential decay
model to evaluate the data on bacterial counts during 5 days of
mono-therapy. The validity of this approach was tested using data
from three previously published studies. For patients treated with
isoniazid 300 mg daily, the values for the time taken to reduce
the viable count by 50% (vt50)
measured in days were, from a Kenyan study 0.58 days S.E.M. 0.18,
from a Tanzanian study 0.41 days S.E.M. 0.04, and
from a United States study 0.55 days S.E.M. 0.12.
These differences were not statistically significant (P = 0.77
Kruskal-Wallis non-parametric ANOVA). Mean values of vt50 for all of the major anti-tuberculosis
agents showed that there was an overlapping spectrum of activity
from isoniazid 300 mg (vt50 0.58
days) to para-amino-salicylic acid (vt50 2.9
days) The variation between column means was greater than could
be expected by chance (P = 0.0002 Kruskal-Wallis
non-parametric ANOVA). From this, we conclude that the reiterative
exponential decay model permits comparison between the data obtained
in different centres and would allow the activity of a new drug
to be compared with that of the currently available agents.
Keywords: tuberculosis, clinical trials, Phase II, mathematical
models
A multicentre comparison of a novel surrogate marker
for determining the specific potency of anti-tuberculosis drugs
2 Mycobacteriology
Clinical Reference Laboratory, National Jewish Medical and Research Center,
Denver, CO 80206, USA
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