Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis.
The creation of new chemotherapeutic regimens that permit shortening the duration of treatment is a major priority for antituberculosis drug development. In this study, we used the murine model of experimental tuberculosis therapy to determine whether incorporation of the investigational new nitroimidazopyran PA-824 into the standard first-line regimen has the potential to shorten the 6-month duration of treatment. As demonstrated previously, PA-824 alone had significant bactericidal activity over the first 2 months of treatment. Moreover, the substitution of PA-824 for isoniazid led to significantly lower lung CFU counts after 2 months of treatment and to more rapid culture-negative conversion compared to the standard regimen of rifampin, isoniazid, and pyrazinamide. Despite this, there was no difference in the proportion of mice relapsing after completing 6 months of therapy (2 of 19 mice treated with PA-824 in place of isoniazid relapsed versus 0 of 46 mice treated with the standard regimen). Meanwhile, no other PA-824-containing regimen tested was superior to the standard regimen on any assessment. Thus, we were unable to establish a clear role for PA-824 in a treatment-shortening regimen that includes two or more of the current first-line drugs. Future preclinical studies should include the evaluation of novel combinations of PA-824 with new drug candidates in addition to existing antituberculosis drugs for their potential to substantially improve the treatment of both drug-susceptible and multidrug-resistant tuberculosis.
Nuermberger
Eric
E
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. enuermb@jhmi.edu
Rosenthal
Ian
I
Tyagi
Sandeep
S
Williams
Kathy N
KN
Almeida
Deepak
D
Peloquin
Charles A
CA
Bishai
William R
WR
Grosset
Jacques H
JH
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000494:pharmacology; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004977:Ethambutol / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D007538:Isoniazid / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development* / Q000302:isolation & purification; D009593:Nitroimidazoles / Q000008:administration & dosage* / Q000494:pharmacology; D011718:Pyrazinamide / Q000008:administration & dosage / Q000494:pharmacology; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology; D055502:Secondary Prevention; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D009593:Nitroimidazoles; C410767:pretomanid; D011718:Pyrazinamide; D004977:Ethambutol; D007538:Isoniazid; D012293:Rifampin