Evaluation of Moxifloxacin-Containing Regimens in Pathologically Distinct Murine Tuberculosis Models

Abstract

dIn the recently concluded REMox-TB trial, two 4-month moxifloxacin-containing regimens did not meet the criteria for noninferiority compared to the current 6-month first-line regimen to treat tuberculosis (TB). Despite the disappointing result, this phase 3 clinical trial provides a rare opportunity to gauge the predictive accuracy of the nonclinical models used to support regimen development. In parallel with the REMox-TB trial, we compared the efficacy of the same three regimens against chronic TB infection in the commonly used BALB/c mouse strain and in C3HeB/FeJ mice, which have attracted recent interest as a nonclinical efficacy model because they develop caseous lung lesions which may better resemble human TB. In long-term treatment experiments at two institutions, using low-dose aerosol infection models with 6-to 8-week incubation periods in both mouse strains, control mice received rifampin, isoniazid, pyrazinamide, and ethambutol (RHZE), and test mice received the same regimen with moxifloxacin replacing isoniazid (RMZE) or ethambutol (RHZM). Outcome measures were lung CFU counts during treatment and relapse after various durations of treatment. At both institutions and in both mouse strains, RMZE and RHZM reduced by approximately 1 month and 0 to 1 month, respectively, the treatment duration needed to produce the same relapse rate as RHZE. These results demonstrating generally similar treatment-shortening effects of the moxifloxacin-containing regimens in each mouse strain, with effect sizes consistent with the REMox-TB trial results, reinforce the predictive value of murine models for TB regimen development.A nimal models provide a critical bridge between in vitro studies and human clinical trials. Mice have served as models for evaluating the efficacy of new antituberculosis drugs and regimens for more than 50 years. The treatment-shortening potential of rifampin (RIF) and pyrazinamide (PZA) was forecast in mice, as was the lack of such sterilizing activity for streptomycin, isoniazid (INH), ethambutol (EMB) and second-line agents developed up until the 1990s (1-3). However, interspecies differences in the spectrum of lung pathology caused by Mycobacterium tuberculosis infection have fueled concerns that mouse models may not accurately represent the efficacy of new antituberculosis drugs or regimens (4). Specifically, it is well known that commonly used mouse strains infected with M. tuberculosis do not develop caseous necrosis and cavitation, which are pathological hallmarks of pulmonary tuberculosis (TB) in humans. If such lesions affect drug exposures at the site of infection or if a microenvironmental condition associated with caseous necrosis (e.g., hypoxia, nutrient depletion, and altered pH) is a determinant of bacterial persistence or drug activation or activity, then the sterilizing activity of new TB drug candidates could be misjudged in mice. Recently, C3HeB/FeJ mice have attracted interest because, in contrast to commonly used mouse strains, they develop caseating granulomas, caseous pne...

Moxifloxacin Replacement in Contemporary Tuberculosis Drug Regimens Is Ineffective against Persistent Mycobacterium tuberculosis in the Cornell Mouse Model

“…The limit of detection was 3 CFU/organ. greater therapeutic efficacy and lower relapse rates achieved in this study with the regimen in which moxifloxacin replaced isoniazid than with the standard regimen are consistent with previous reports (5)(6)(7)(8). De Groote et al demonstrated that replacement of isoniazid by moxifloxacin in the standard regimen gave rise to a 63% disease relapse rate (6).…”

The role of moxifloxacin in tuberculosis therapy

“…This is disappointing and context is provided by a comparison with earlier trials in table 1. Post hoc reports have suggested that the outcome could have been predicted by a different mouse model: a chronic TB low-dose inhalation infection in BALB/c mice and in C3HeB/FeJ mice, which unlike other strains develop caseous lung lesions and may better resemble human TB [52]. A statistical explanation is that the best of the phase IIb studies reported a hazard ratio for the time to culture conversion for the moxifloxacin-containing regimen, as compared with the standard regimen, of 1.73 (95% CI 1.15-2.60), suggesting a shorter duration regimen might be possible [36].…”

Genomic Analysis of the Evolution of Fluoroquinolone Resistance in Mycobacterium tuberculosis Prior to Tuberculosis Diagnosis

“…The later-generation fluoroquinolones (FQs), particularly moxifloxacin, have shown a great deal of promise in animal models (2) and are currently recommended by the WHO as second-line drugs for the treatment of drug-resistant TB (3); however, they are not currently licensed for the treatment of drug-sensitive TB. Recently, three separate clinical trials evaluated a potential role for FQs in shortening the duration of therapy for drug-sensitive TB from the current 6 months to 4 months, an important goal aimed at simplifying TB therapy and reducing default rates, which contribute to the emergence of drug resistance (4)(5)(6).…”