RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
Authors: Ian M Rosenthal; Rokeya Tasneen; Charles A Peloquin; Ming Zhang; Deepak Almeida; Khisimuzi E Mdluli; Petros C Karakousis; Jacques H Grosset; Eric L Nuermberger Journal: Antimicrob Agents Chemother Date: 2012-06-04 Impact factor: 5.191
Authors: Rokeya Tasneen; Si-Yang Li; Charles A Peloquin; Dinesh Taylor; Kathy N Williams; Koen Andries; Khisimuzi E Mdluli; Eric L Nuermberger Journal: Antimicrob Agents Chemother Date: 2011-09-19 Impact factor: 5.191
Authors: J W C Alffenaar; T van der Laan; S Simons; T S van der Werf; P J van de Kasteele; H de Neeling; D van Soolingen Journal: Antimicrob Agents Chemother Date: 2011-01-03 Impact factor: 5.191
Authors: Kathy Williams; Austin Minkowski; Opokua Amoabeng; Charles A Peloquin; Dinesh Taylor; Koen Andries; Robert S Wallis; Khisimuzi E Mdluli; Eric L Nuermberger Journal: Antimicrob Agents Chemother Date: 2012-04-02 Impact factor: 5.191
Authors: Amit Kaushik; Abigail M Heuer; Drew T Bell; Jeffrey C Culhane; David C Ebner; Nicole Parrish; J Thomas Ippoliti; Gyanu Lamichhane Journal: Bioorg Med Chem Lett Date: 2016-06-09 Impact factor: 2.823
Authors: Zahoor Ahmad; Eric L Nuermberger; Rokeya Tasneen; Michael L Pinn; Kathy N Williams; Charles A Peloquin; Jacques H Grosset; Petros C Karakousis Journal: J Antimicrob Chemother Date: 2010-01-31 Impact factor: 5.790