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Published ahead of print on August 11, 2004, doi:10.1164/rccm.200407-885OC
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American Journal of Respiratory and Critical Care Medicine Vol 170. pp. 1131-1134, (2004)
© 2004 American Thoracic Society
doi: 10.1164/rccm.200407-885OC

Original Article

Moxifloxacin-containing Regimens of Reduced Duration Produce a Stable Cure in Murine Tuberculosis

Eric L. Nuermberger, Tetsuyuki Yoshimatsu, Sandeep Tyagi, Kathy Williams, Ian Rosenthal, Richard J. O'Brien, Andrew A. Vernon, Richard E. Chaisson, William R. Bishai and Jacques H. Grosset

Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Foundation for Innovative New Diagnostics, Geneva, Switzerland; and Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, Georgia

Correspondence and requests for reprints should be addressed to Eric L. Nuermberger, M.D., 1503 East Jefferson Street, Baltimore, MD 21231–1002. E-mail: enuermb{at}jhmi.edu


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In a recent experimental study using the mouse model of tuberculosis, treatment with a combination of rifampin, moxifloxacin, and pyrazinamide was able to shorten the time to negative lung cultures by up to 2 months compared with the standard regimen of rifampin, isoniazid, and pyrazinamide. To confirm that this substitution of moxifloxacin for isoniazid permits a shorter duration of treatment, a second study was performed in which mice were assessed for relapse after treatment with combination therapy for 3, 4, 5, or 6 months. Although no relapse was observed among mice treated for at least 4 months with rifampin, moxifloxacin, and pyrazinamide, mice treated with rifampin, isoniazid, and pyrazinamide required 6 months of treatment before no relapse could be detected. For mice treated with rifampin, moxifloxacin, and pyrazinamide, similar efficacy was noted whether pyrazinamide was administered for 1 month, 2 months, or the entire duration of therapy. These results suggest that the use of rifampin, moxifloxacin, and pyrazinamide may substantially shorten the duration of therapy needed to cure human tuberculosis and that the full benefit of pyrazinamide in this regimen may be realized after just 1 month of treatment.

Key Words: fluoroquinolone • mouse • moxifloxacin • pyrazinamide • tuberculosis

The 8-methoxyfluoroquinolone moxifloxacin has potent activity against Mycobacterium tuberculosis in vitro in the mouse model and in humans as measured by early bactericidal activity (1–7). Up to now, it has been used as a second-line drug for the treatment of patients with multidrug-resistant tuberculosis or patients intolerant of first-line agents. In a recent study, we assessed its potential as a first-line drug in the mouse model of tuberculosis. We found that the treatment of infected mice with a combination of rifampin (R), moxifloxacin (M), and pyrazinamide (Z) for 2 months, followed by rifampin and moxifloxacin for 4 months (regimen abbreviated as 2RMZ/4RM) resulted in a shorter time to lung culture conversion than did treatment with the standard regimen of rifampin, isoniazid (H), and pyrazinamide for 2 months followed by rifampin and isoniazid for 4 months (regimen abbreviated as 2RHZ/4RH) (8). Mice receiving 2RMZ/4RM were nearly all culture negative after just 3 months of therapy, whereas no mouse receiving 2RHZ/4RH was culture negative before receiving 5 months of therapy. Although these data suggest that the sterilizing activity of the standard isoniazid-containing regimen could be greatly improved by replacing isoniazid with moxifloxacin, the study was not designed to determine whether the duration of treatment might be shortened by the use of moxifloxacin-containing regimens because all mice received 6 months of therapy before being assessed for relapse. Because the frequency of relapse is the most stringent measure of sterilizing activity, the primary objective of this study was to characterize better the potential of a RMZ-based regimen to permit shortening the duration of therapy by assessing mice for relapse after treatment with abbreviated treatment regimens.

A second issue raised by the previous study regards the optimal duration of treatment with pyrazinamide. The addition of pyrazinamide to regimens containing rifampin and isoniazid permits shortening the duration of modern, short-course therapy from 9 to 6 months (9). It has been well demonstrated that the maximum benefit of pyrazinamide is achieved in the first 2 months of therapy and that continued administration together with rifampin and isoniazid beyond the first 2 months results in no beneficial effect (10–12). However, the minimum duration of therapy necessary to realize the benefit of pyrazinamide has not been determined. Moreover, it remains unclear whether longer treatment with pyrazinamide would be beneficial in the absence of isoniazid (i.e., with the RMZ regimen). On one hand, the use of pyrazinamide for longer than 2 months has the potential to increase further the sterilizing activity of the RMZ regimen. On the other hand, shorter durations of pyrazinamide may be easier to administer and better tolerated in humans. To address the issue of the optimal duration of pyrazinamide administration, we studied additional treatment regimens in which pyrazinamide was combined with RM for only the first month or for the entire duration of treatment.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Antimicrobials
Drugs were obtained and stock solutions prepared as previously described (8).

M. tuberculosis Strain
Strain H37Rv expressing firefly luciferase (after transformation with the integrating plasmid pGS16) was kindly provided by W. Jacobs (13). At that time, there were no published or unpublished data to suggest that it is attenuated in virulence compared with the standard H37Rv laboratory strain. The strain was passaged in mice, subcultured in Middlebrook 7H9 broth (Fisher, Pittsburgh, PA), and used for aerosol infection when the optical density at 600 nm was 0.9. Minimum inhibitory concentrations were rifampin, 0.25 µg/ml; isoniazid, 0.1 µg/ml; and moxifloxacin, 0.5 µg/ml on 7H10 medium; and pyrazinamide, 10 µg/ml on Löwenstein-Jensen medium (pH 5.5).

Aerosol Infection
Seven-week-old female BALB/c mice (Charles River, Wilmington, MA) were infected (Day 19) in a Middlebrook Inhalation Exposure System (Glas-col Inc., Terre Haute, IN). Three successive runs were performed. Previous experience has confirmed uniform infections with each run (8).

Treatment
After infection, mice were randomized into four treatment groups. The control group received the standard 6-month regimen, 2RHZ/4RH. The three experimental groups received 5-month RMZ-based regimens in which pyrazinamide was given for 1 month (1RMZ/4RM), for 2 months (2RMZ/3RM), or for the entire duration of therapy (5RMZ). Seven additional untreated mice went untreated and were killed 1 month into treatment as negative control animals. For consistency, each "month" of treatment lasted 28 days.

Treatment began 19 days after infection (D0), when the bacillary burden is typically 107–108 cfu, like that in a human tuberculous pulmonary cavity (14, 15). Drugs were administered daily by gavage in the following dosages (mg/kg): rifampin, 10; isoniazid, 25; pyrazinamide, 150; and moxifloxacin, 100, as previously described (8).

Assessment of Treatment Efficacy
Four untreated mice from each of three aerosol runs were killed on the day after aerosol infection and D0 as pretreatment control animals. Six mice from each treatment group were killed after 2 and 4 weeks of therapy and then monthly to determine cfu counts from lung and spleen homogenates. After 3, 4, 5, and 6 months of therapy, an additional 12–16 mice from each group went untreated for 3 additional months before being killed to measure the proportion of mice with culture-positive relapse; cfu counts were performed as previously described (5, 8). Mouse body weights, spleen weights, and assessments of gross lung lesions were also performed as previously described (8).

Statistical Analysis
The proportion of mice with culture-proven relapse was determined at each time point. Multiple pairwise comparisons between groups were made using Fisher's exact test (STATA 7.0, STATA Corp., College Station, TX). Bonferroni's procedure was used to adjust the type I error rate for multiple comparisons to maintain an overall error rate of 0.05. The aggregate proportion of relapsing mice in all groups receiving moxifloxacin was also compared with that of mice treated with the standard regimen.

Cfu counts were log-transformed as log10(x + 1), where x equals the total organ cfu count. Multiple pairwise comparisons of group means were performed by one-way analysis of variance with Bonferroni's post-test (GraphPad InStat version 3.05, San Diego, CA).


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Body Weight, Spleen Weight, and Gross Appearance of the Lung
Body weight, spleen weight, and gross appearance of the lung were assessed for each group at each time point. There were no significant differences in body weight between groups at any time point.

At D0, the mean spleen weight was 105 ± 18 mg. After 2 weeks of treatment, the mean spleen weights were 124 ± 38 and 81 ± 30 mg in the groups treated with RHZ and RMZ, respectively. Neither value was significantly different from the D0 control, but the difference between the RHZ and RMZ groups was significant by unpaired t test (p < 0.05). After 1 month of treatment, the mean spleen weights were 192 ± 15, 93 ± 10, and 89 ± 9 mg for mice receiving no treatment, RHZ, or RMZ, respectively. The differences between treated and untreated animals were highly significant (p < 0.0001), but the mean spleen weights were not different between mice receiving RHZ- and RMZ-based regimens at this or any later time point.

The gross examination of the lung surface at D0 revealed multiple tubercles in both lungs, consistent with heavy infection. After 1 month, the lungs of untreated mice had increased in size, and the lesions had begun to coalesce. In contrast, the lungs of treated mice had 50–100 discrete visible lesions that were smaller than those seen at the onset of treatment. These lesions were progressively fewer in number after 2 and 3 months of treatment and were no longer visible after 4 months of treatment. There were no apparent differences in gross lung appearance between RHZ- and RMZ-treated mice or between mice that were later found to relapse and those that did not.

Organ cfu Counts during Treatment
The day after aerosol infection, the mean log10 cfu count (± SD) in the lungs was 3.81 ± 0.05. At D0, the mean log10 cfu count in the lungs had increased to 6.86 ± 0.58, and the spleen cfu count was 3.10 ± 0.48. The mean log10 cfu counts from lung and spleen homogenates are presented in Tables 1 and 2, respectively. Untreated animals had no change in lung cfu counts after 1 month, whereas the spleen cfu counts increased by approximately one log. Treatment with RMZ reduced the lung cfu counts more rapidly than did treatment with RHZ, with statistically significant differences seen at the 2- and 4-week time points. These findings were mirrored in the spleen cfu counts. Although the difference in spleen cfu counts at 2 weeks was not quite statistically significant (p = 0.10), all six mice treated with RMZ had negative spleen cultures at 4 weeks, whereas all mice treated with RHZ had positive cultures. By 2 months, the lung cfu counts had been greatly reduced by all treatments, and significant differences could no longer be appreciated, whether mice received 2RHZ, 2RMZ, or 1RMZ/1RM. After 3 or more months of treatment, all mice had negative lung cultures.


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  		TABLE 1. Mean log10 cfu counts* from lung homogenates

 

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  		TABLE 2. Mean log10 cfu counts* from spleen homogenates

 
Relapse after Treatment Completion
The proportion of mice with culture-positive relapse after the end of treatment was determined for each regimen (Table 3). There were significant differences noted in the frequency of relapse between RMZ- and RHZ-treated mice after 3 months of treatment. The group treated with 2RMZ/1RM had significantly fewer relapses than the group treated with 2RHZ/1RH (p < 0.001) even when the analysis was corrected for multiple comparisons. Both the 1RMZ/2RM and 3RMZ groups also had fewer relapses compared with the group treated with the standard regimen (p < 0.01), but the statistical significance of the difference was lost in the corrected analysis. After 4 months of therapy, there were no relapses among mice treated with any one of the three RMZ-based regimens, whereas 5 of 12 mice treated with the standard regimen relapsed. Again, this difference was statistically significant before, but not after, correction for multiple comparisons (p < 0.05). When analyzed together, mice receiving any RMZ-based regimen for 3 or 4 months were less likely to relapse than were mice receiving the standard regimen for the same duration (p < 0.001). In other words, mice receiving any of the three RMZ-based regimens achieved a stable cure more rapidly than those receiving the standard regimen. Although stable cure was achieved in all mice receiving any one of the three RMZ-based regimens for 4 months, treatment with the standard regimen required 6 months of therapy for stable cure of all mice. No differences could be discerned between any of the RMZ-based regimens at any time point.


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  		TABLE 3. Proportions of mice relapsing after treatment completion

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, we directly measured the proportion of mice with culture-positive relapse after various durations of treatment with RMZ- and RHZ-based regimens. This design allowed us to determine better the extent to which use of an RMZ-based regimen would permit shortening the duration of therapy. Although we observed no relapse among mice treated for at least 4 months with 2RMZ/2RM, mice treated with 2RHZ/4RH required 6 months of treatment before no relapse could be detected. In other words, stable cure was achieved 2 months earlier in mice treated with an RMZ-based regimen rather than the standard RHZ-based regimen. The magnitude of this shortening effect is similar to that achieved with the introduction of pyrazinamide into first-line use. It is also worth noting that the moxifloxacin dose used in this experiment (100 mg/kg) is more likely to have underestimated, rather than overestimated, the activity of moxifloxacin expected in humans receiving the standard 400-mg dose (8, 16). Therefore the findings in mice are likely to be reproducible in humans, for reasons discussed in our previous article (8).

We also found similar efficacy for all RMZ-based regimens whether pyrazinamide was administered for 1 month, 2 months, or the entire duration of therapy. Although inclusion of pyrazinamide during the intensive phase clearly adds to the sterilizing activity of rifampin and isoniazid in the mouse model (15) and in the treatment of human disease, the duration of therapy necessary to derive its maximum benefit has never been determined with precision. Randomized clinical trials have failed to demonstrate any benefit to extending the use of pyrazinamide beyond the first 2 months of therapy when the continuation regimen included rifampin and isoniazid (10–12), but the minimum duration of therapy necessary to realize the benefits of pyrazinamide remains unknown. Two clinical trials have compared a 1-month daily intensive phase regimen of streptomycin (S), isoniazid, rifampin, and pyrazinamide to a 2-month intensive phase regimen with the same drugs before switching to a three times weekly regimen of rifampin and isoniazid (17–19). The two regimens had similar relapse rates in both studies. Although the proportion of subjects with conversion to negative sputum cultures was lower at 2 months for subjects receiving the 1-month intensive phase (85% vs. 99%) in one of the two studies, 97% of subjects receiving the 1-month intensive phase had negative sputum cultures after 3 months of therapy (17). The delayed sputum conversion in patients receiving the 1-month intensive phase regimen could have been related to the receipt of only 1 month of pyrazinamide, only 1 month of streptomycin, and/or only 1 month of daily rifampin and isoniazid before the intermittent continuation phase regimen. However, the cure rates were not negatively affected (18). The results of this trial should not discourage the evaluation of shorter durations of pyrazinamide administration in future clinical trials of RMZ-based regimens. If our results with the use of only 1 month of pyrazinamide in the intensive phase of therapy can be confirmed in clinical trials, the result would be regimens that would be easier to deliver and would likely have fewer adverse effects. This may be critical if the recent finding that the combination of rifampin and pyrazinamide appears to be more hepatotoxic than RHZ also applies when RMZ is compared with RHZ (20).

There are two caveats to consider in the interpretation of these results. First, despite initial passage in the mouse, the strain of M. tuberculosis used for infection appeared to be of somewhat reduced virulence because the bacillary burden in the lungs increased by only three logs, rather than the expected four logs, during the period before treatment. The lower bacillary burden at the onset of treatment resulted in more rapid attainment of negative lung cultures compared with our previous study. Although we cannot exclude the possibility that the diminished replication capacity of the organism differentially favored one regimen over another, we believe it is unlikely. Second, the relatively small numbers of mice used to determine the frequency of relapse limited the power to detect small differences between treatment groups. These two limitations are being addressed by a study that involves larger numbers of mice for relapse determinations and infection with a mouse-passaged isolate of the standard strain, M. tuberculosis H37Rv.

The development of an efficacious ultrashort course (i.e., <= 4 months) regimen for the treatment of TB in humans is expected to promote treatment completion rates and facilitate the worldwide implementation of directly observed treatment programs (21). RMZ-based regimens have the potential to achieve this goal. The TB Trials Consortium of the Centers for Disease Control and Prevention is currently enrolling patients in a phase 2 clinical trial comparing a 2-month intensive phase regimen of RHZM versus RHZ + ethambutol (E) (i.e., moxifloxacin replacing ethambutol). The results will shed light on the additive activity and tolerability of moxifloxacin. However, the results of our previous study (8) suggest that replacing isoniazid with moxifloxacin would provide a greater benefit than adding moxifloxacin to RHZ. This hypothesis should be addressed in future clinical trials.


   FOOTNOTES
 
Supported by the Global Alliance for TB Drug Development, the National Institutes of Health (supplement to grant AI43846), and Bayer (moxifloxacin).

Conflict of Interest Statement: E.L.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; T.Y. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; S.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; K.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; I.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.J.O. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; A.A.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; R.E.C. has served as a consultant for Bayer on therapeutic uses of recombinant interleukins in human immunodeficiency virus–infected patients receiving a compensation of $800 in 2002 and 2003; W.R.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript; J.H.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form July 8, 2004; accepted in final form August 10, 2004


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