Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis.
BACKGROUND
We recently reported strong bactericidal activity of the oxazolidinone PNU-100480 and its ability to increase the initial bactericidal effect of various combinations of first-line tuberculosis drugs and moxifloxacin in a murine model.


OBJECTIVE
To investigate whether the addition of PNU-100480 to the standard first-line regimen of rifampin, isoniazid, and pyrazinamide could shorten the duration of treatment necessary to prevent relapse after treatment discontinuation.


METHODS
Following aerosol infection with Mycobacterium tuberculosis H37Rv and a 13-day incubation period, control mice were treated with the first-line regimen while test mice received the same regimen with PNU-100480 or linezolid added for the first 2 or 4 months. Efficacy was assessed on the basis of quantitative cultures of lung homogenates performed monthly during treatment and 3 months after completion of 3, 4, 5, or 6 months of treatment to determine the relapse rate.


RESULTS
After 2 months of treatment, mice receiving PNU-100480 in addition to the first-line regimen had lung CFU counts two orders of magnitude lower than control mice receiving the first-line regimen alone. Relapse rates after 4 months of treatment were 90, 35, and 5% when PNU-100480 was added to the first-line regimen for 0, 2, and 4 months, respectively. When the total treatment duration was 3 months, relapse rates were 85 and 35 to 45% when mice received PNU-100480 for 2 and 3 months, respectively; all control mice remained culture positive at the time of treatment completion with 17 to 72 CFU per lung. Addition of linezolid to the first-line regimen had an antagonistic effect resulting in higher CFU counts and failure to render mice culture-negative in 4 months of treatment.


CONCLUSIONS
Together with previous findings, these results confirm that PNU-100480, which is now in Phase I clinical testing, has sterilizing activity in the murine model and suggest that it may be capable of shortening treatment duration for drug-susceptible as well as drug-resistant tuberculosis in humans.
Williams
Kathy N
KN
Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Brickner
Steven J
SJ
Stover
Charles K
CK
Zhu
Tong
T
Ogden
Adam
A
Tasneen
Rokeya
R
Tyagi
Sandeep
S
Grosset
Jacques H
JH
Nuermberger
Eric L
EL
D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003114:Colony-Forming Units Assay; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D000069349:Linezolid; D008168:Lung / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D023303:Oxazolidinones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013997:Time Factors; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000473:pathology
D000081:Acetamides; D000995:Antitubercular Agents; D023303:Oxazolidinones; C543015:PNU-100480; D000069349:Linezolid