Combination chemotherapy with the nitroimidazopyran PA-824 and first-line drugs in a murine model of tuberculosis.

Abstract

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.

• Authors: Eric Nuermberger, Ian Rosenthal, Sandeep Tyagi, Kathy N Williams, Deepak Almeida, Charles A Peloquin, William R Bishai, Jacques H Grosset
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 50 Issue 8 Pg. 2621-5 (Aug 2006) ISSN: 0066-4804 [Print] United States
• PMID: 16870750 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antitubercular
• Antitubercular Agents
• Nitroimidazoles
• pretomanid
• Pyrazinamide
• Ethambutol
• Isoniazid
• Rifampin

Topics

• Animals
• Antibiotics, Antitubercular (administration & dosage, pharmacology)
• Antitubercular Agents (administration & dosage, pharmacology)
• Disease Models, Animal
• Drug Therapy, Combination
• Ethambutol (administration & dosage, pharmacology)
• Female
• Isoniazid (administration & dosage, pharmacology)
• Mice
• Mice, Inbred BALB C
• Mycobacterium tuberculosis (drug effects, growth & development, isolation & purification)
• Nitroimidazoles (administration & dosage, pharmacology)
• Pyrazinamide (administration & dosage, pharmacology)
• Rifampin (administration & dosage, pharmacology)
• Secondary Prevention
• Time Factors
• Tuberculosis, Pulmonary (drug therapy, microbiology)