Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, mycobacterium tuberculosis in the guinea pig

Zahoor Ahmad, Lee G. Klinkenberg, Michael L. Pinn, Mostafa M. Fraig, Charles A. Peloquin, William Ramses Bishai, Eric Nuermberger, Jacques H. Grosset, Petros Karakousis

Research output: Contribution to journalArticle

Abstract

The marked reduction in the potent early bactericidal activity of isoniazid during the initial phase of antituberculosis (anti-TB) therapy has been attributed not only to the depletion of logarithmically growing bacilli but also to the emergence of isoniazid resistance. We studied the anti-TB activity of isoniazid and its ability to select for drug-resistant mutant strains in guinea pigs, in which the histopathology of TB closely resembles that of human TB. Prior mouse passage did not appear to enhance the virulence of Mycobacterium tuberculosis in guinea pigs. The human-equivalent dose of isoniazid was determined to be 60 mg/kg. Although isoniazid therapy caused rapid killing of bacilli in guinea pig lungs during the first 14 days of administration and rescued guinea pigs from acute death, its activity was dramatically reduced thereafter. This reduction in activity was not associated with the emergence of isoniazid-resistant mutant strains but, rather, with the selection of phenotypically tolerant "persisters."

Original languageEnglish (US)
Pages (from-to)1136-1143
Number of pages8
JournalJournal of Infectious Diseases
Volume200
Issue number7
DOIs
StatePublished - Oct 1 2009

Fingerprint

Multidrug-Resistant Tuberculosis
Isoniazid
Mycobacterium tuberculosis
Guinea Pigs
Pharmaceutical Preparations
Bacillus
Virulence
Lung
Therapeutics

ASJC Scopus subject areas

  • Infectious Diseases
  • Immunology and Allergy

Cite this

Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, mycobacterium tuberculosis in the guinea pig. / Ahmad, Zahoor; Klinkenberg, Lee G.; Pinn, Michael L.; Fraig, Mostafa M.; Peloquin, Charles A.; Bishai, William Ramses; Nuermberger, Eric; Grosset, Jacques H.; Karakousis, Petros.

In: Journal of Infectious Diseases, Vol. 200, No. 7, 01.10.2009, p. 1136-1143.

Research output: Contribution to journalArticle

Ahmad, Zahoor ; Klinkenberg, Lee G. ; Pinn, Michael L. ; Fraig, Mostafa M. ; Peloquin, Charles A. ; Bishai, William Ramses ; Nuermberger, Eric ; Grosset, Jacques H. ; Karakousis, Petros. / Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, mycobacterium tuberculosis in the guinea pig. In: Journal of Infectious Diseases. 2009 ; Vol. 200, No. 7. pp. 1136-1143.
@article{b443725c807a4bbcb6205cfab39a1829,
title = "Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, mycobacterium tuberculosis in the guinea pig",
abstract = "The marked reduction in the potent early bactericidal activity of isoniazid during the initial phase of antituberculosis (anti-TB) therapy has been attributed not only to the depletion of logarithmically growing bacilli but also to the emergence of isoniazid resistance. We studied the anti-TB activity of isoniazid and its ability to select for drug-resistant mutant strains in guinea pigs, in which the histopathology of TB closely resembles that of human TB. Prior mouse passage did not appear to enhance the virulence of Mycobacterium tuberculosis in guinea pigs. The human-equivalent dose of isoniazid was determined to be 60 mg/kg. Although isoniazid therapy caused rapid killing of bacilli in guinea pig lungs during the first 14 days of administration and rescued guinea pigs from acute death, its activity was dramatically reduced thereafter. This reduction in activity was not associated with the emergence of isoniazid-resistant mutant strains but, rather, with the selection of phenotypically tolerant {"}persisters.{"}",
author = "Zahoor Ahmad and Klinkenberg, {Lee G.} and Pinn, {Michael L.} and Fraig, {Mostafa M.} and Peloquin, {Charles A.} and Bishai, {William Ramses} and Eric Nuermberger and Grosset, {Jacques H.} and Petros Karakousis",
year = "2009",
month = "10",
day = "1",
doi = "10.1086/605605",
language = "English (US)",
volume = "200",
pages = "1136--1143",
journal = "Journal of Infectious Diseases",
issn = "0022-1899",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, mycobacterium tuberculosis in the guinea pig

AU - Ahmad, Zahoor

AU - Klinkenberg, Lee G.

AU - Pinn, Michael L.

AU - Fraig, Mostafa M.

AU - Peloquin, Charles A.

AU - Bishai, William Ramses

AU - Nuermberger, Eric

AU - Grosset, Jacques H.

AU - Karakousis, Petros

PY - 2009/10/1

Y1 - 2009/10/1

N2 - The marked reduction in the potent early bactericidal activity of isoniazid during the initial phase of antituberculosis (anti-TB) therapy has been attributed not only to the depletion of logarithmically growing bacilli but also to the emergence of isoniazid resistance. We studied the anti-TB activity of isoniazid and its ability to select for drug-resistant mutant strains in guinea pigs, in which the histopathology of TB closely resembles that of human TB. Prior mouse passage did not appear to enhance the virulence of Mycobacterium tuberculosis in guinea pigs. The human-equivalent dose of isoniazid was determined to be 60 mg/kg. Although isoniazid therapy caused rapid killing of bacilli in guinea pig lungs during the first 14 days of administration and rescued guinea pigs from acute death, its activity was dramatically reduced thereafter. This reduction in activity was not associated with the emergence of isoniazid-resistant mutant strains but, rather, with the selection of phenotypically tolerant "persisters."

AB - The marked reduction in the potent early bactericidal activity of isoniazid during the initial phase of antituberculosis (anti-TB) therapy has been attributed not only to the depletion of logarithmically growing bacilli but also to the emergence of isoniazid resistance. We studied the anti-TB activity of isoniazid and its ability to select for drug-resistant mutant strains in guinea pigs, in which the histopathology of TB closely resembles that of human TB. Prior mouse passage did not appear to enhance the virulence of Mycobacterium tuberculosis in guinea pigs. The human-equivalent dose of isoniazid was determined to be 60 mg/kg. Although isoniazid therapy caused rapid killing of bacilli in guinea pig lungs during the first 14 days of administration and rescued guinea pigs from acute death, its activity was dramatically reduced thereafter. This reduction in activity was not associated with the emergence of isoniazid-resistant mutant strains but, rather, with the selection of phenotypically tolerant "persisters."

UR - http://www.scopus.com/inward/record.url?scp=70349330225&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349330225&partnerID=8YFLogxK

U2 - 10.1086/605605

DO - 10.1086/605605

M3 - Article

C2 - 19686043

AN - SCOPUS:70349330225

VL - 200

SP - 1136

EP - 1143

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

SN - 0022-1899

IS - 7

ER -