Biphasic kill curve of isoniazid reveals the presence of drug-tolerant, not drug-resistant, Mycobacterium tuberculosis in the guinea pig.
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."
Ahmad
Zahoor
Z
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21289, USA.
Klinkenberg
Lee G
LG
Pinn
Michael L
ML
Fraig
Mostafa M
MM
Peloquin
Charles A
CA
Bishai
William R
WR
Nuermberger
Eric L
EL
Grosset
Jacques H
JH
Karakousis
Petros C
PC
D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial; D006168:Guinea Pigs; D007538:Isoniazid / Q000494:pharmacology*; D008168:Lung / Q000382:microbiology / Q000473:pathology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000472:pathogenicity; D013997:Time Factors; D014376:Tuberculosis / Q000382:microbiology*; D014774:Virulence
D000995:Antitubercular Agents; D007538:Isoniazid