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Antimicrobial Agents and Chemotherapy, January 1999, p. 85-89, Vol. 43, No. 1
Center for Tuberculosis Research,
Received 3 August 1998/Returned for modification 1 September
1998/Accepted 20 October 1998
Moxifloxacin (BAY12-8039) is a new 8-methoxyquinolone shown to be
active against Mycobacterium tuberculosis in vitro. We
tested moxifloxacin for activity in mice against M. tuberculosis CSU93, a highly virulent, recently
isolated clinical strain. The MIC of moxifloxacin for the CSU93 strain
was 0.25 µg/ml. The serum moxifloxacin concentration after
oral administration in mice peaked within 0.25 h, reaching 7.8 µg/ml with doses of 100 mg/kg of body weight; the maximum
concentration and the analysis of the area under the concentration-time
curve revealed dose dependency. When mice were infected with a
sublethal inoculum of mycobacteria and then treated with moxifloxacin
at 100 mg/kg per day for 8 weeks, the log10 CFU counts in
the organs of treated mice were significantly lower than those for the
control group (0.6 ± 0.2 versus 5.6 ± 0.3 in the lungs and
1.5 ± 0.7 versus 4.9 ± 0.5 in the spleens, respectively;
P < 0.001 in both organs). The effectiveness of moxifloxacin monotherapy was comparable to that seen in mice receiving isoniazid alone. Combination therapy with moxifloxacin plus
isoniazid was superior to that with moxifloxacin or with isoniazid
alone in reducing bacillary counts in the organs studied. Using a
sensitive broth-passage subculture method, we demonstrated that 8 weeks of treatment with moxifloxacin (100 mg/kg per day) or with moxifloxacin plus isoniazid (100 mg/kg and 25 mg/kg, respectively, per day) sterilized the lungs in seven of eight and in eight of eight mice, respectively. Among surviving bacilli isolated from animals infected with a high-titer inoculum and treated for 7 weeks with low-dose moxifloxacin (20 mg/kg per day), breakthrough resistance to
moxifloxacin was not observed. These results indicate that moxifloxacin
is highly effective in reducing M. tuberculosis infection
in mice and has activity comparable to that of isoniazid.
Combination therapy with moxifloxacin and isoniazid was highly
effective, suggesting that moxifloxacin may be useful in multiple-drug
regimens for human tuberculosis.
Tuberculosis remains the leading
cause of death worldwide from any single infectious agent. The
resurgence of tuberculosis in the United States from 1985 to 1992 was
accompanied by an increase in the prevalence of resistance to
first-line antimycobacterial agents, including isoniazid (INH) and
rifampin (5, 6, 19). A survey conducted in New York, N.Y.,
in 1992 showed that 33% of culture-positive patients had
Mycobacterium tuberculosis isolates resistant to one or more
antituberculous drugs and 19% had multiple-drug-resistant tuberculosis
isolates that were resistant to both INH and rifampin (5). A
35-nation study of the global incidence of drug-resistant tuberculosis
found single-drug resistance rates of 36% and multiple-drug resistance
rates of 13% among previously treated patients (16). Serious difficulty in controlling infections caused by drug-resistant tuberculosis has further increased demand for potent new drugs to
counter M. tuberculosis.
Several fluoroquinolones, such as levofloxacin, ofloxacin, and
ciprofloxacin, exhibit MICs of about 1 µg/ml for M. tuberculosis and can attain concentrations in serum that inhibit
M. tuberculosis (8, 9, 10, 18, 23). Clinical
reports have demonstrated efficacy of ofloxacin and ciprofloxacin
against pulmonary tuberculosis, including disease caused by
drug-resistant tubercle bacilli, and the use of these agents as
tuberculosis chemotherapeutics has increased (10, 11, 18,
24). However, the use of ofloxacin and ciprofloxacin is limited
by the development of resistance, which may be related to their
inability to achieve concentrations in serum well in excess of the MIC
for the organism. In addition, long-acting drugs are important for
tuberculosis chemotherapy in view of the importance of directly
observed therapy in preventing nonadherence. Hence, the development of
long-acting quinolones with improved penetration and antituberculous
potency would be valuable for future tuberculosis control efforts.
Moxifloxacin (BAY12-8039) is a new 8-methoxyquinolone with
broad-spectrum activity against gram-positive, gram-negative, and anaerobic bacteria. Its serum half-life permits once-daily dosing in
humans (1, 2, 4, 7, 20, 21, 26). This drug has more potent
in vitro antimicrobial activity than ofloxacin or ciprofloxacin
against gram-positive aerobes, including streptococci and staphylococci
(4), and also against anaerobes, such as Bacteroides
fragilis and Peptostreptococcus and
Clostridium spp. (1). Moxifloxacin also has in
vitro activity comparable to that of rifampin (MIC of ~0.5 µg/ml)
against three strains of M. tuberculosis that are resistant
to one or more of the commonly used antimycobacterial agents and
against a fourth, fully susceptible strain (26). In this
study, we tested moxifloxacin for activity against M. tuberculosis in a murine tuberculosis model using a virulent
clinical isolate (25). We also evaluated its pharmacokinetic properties in mice to determine the effectiveness of a daily dosing regimen in this animal model.
Antibiotics.
Moxifloxacin (BAY12-8039) was provided by the
Bayer Corporation (West Haven, Conn.). Carbenicillin, polymyxin B,
trimethoprim, and INH were purchased from Sigma Chemical Co. (St.
Louis, Mo.), and amphotericin B was purchased from GIBCO Laboratories
(New York, N.Y.).
Bacterial cultivation.
M. tuberculosis CSU93 was
cultivated at 37°C in roller bottles in 7H9-ADC broth (Difco
Laboratories, Detroit, Mich.) supplemented with 0.05% Tween 80. For
animal inoculation, liquid cultures were declumped by brief bath
sonication and settling and then diluted in 7H9-ADC broth. Estimated
titers measured by hemacytometer counts accorded well with plating
dilutions, though the latter were used as the definitive inoculum
titers. Colony counts from mouse organs were performed by using
Middlebrook 7H10-ADC agar plates made selective by addition of
carbenicillin, polymyxin B, trimethoprim, and amphotericin B to final
concentrations of 100 µg/ml, 200 U/ml, 20 µg/ml, and 10 µg/ml,
respectively. Mycobacterial susceptibility testing was performed by use
of the radiometric BACTEC system (Becton Dickinson, Sparks, Md.)
according to standard protocols (17). Susceptibility testing
on in vivo-grown M. tuberculosis from drug-treated mice was
performed by subculturing lung homogenates in selective Middlebrook 7H9
broth at 37°C for 1 week to obtain more than 105 CFU/ml
for BACTEC analysis.
Animal model.
Outbred, female Swiss-Webster mice (5 weeks of
age; weight range, 18 to 20 g) were purchased from Harlan Sprague
Dawley, Inc. (Indianapolis, Ind.), housed in a pathogen-free, biosafety
level 3 environment, and allowed to acclimate to their new environment for at least 2 days prior to infection. Food and water were provided ad
libitum. Infections were produced by intravenous tail vein inoculation
with 0.1 ml of a suspension containing a declumped, diluted, titered
M. tuberculosis preparation. Following infection, mice
were randomly divided into groups (eight mice per group); in our
previous studies this procedure has provided sufficient statistical power. Treatment was initiated 1 week after inoculation (for experiment 1) or on the day following inoculation (for experiment 2). Drugs were administered by esophageal gavage six times weekly; control mice received sterile distilled water by gavage according to
the same schedule. Treatment was continued for 4 or 8 weeks (for
experiment 1) or for 3 or 7 weeks (for experiment 2), at which points
groups of eight mice were euthanized. Lung and spleen colony counts
were determined by homogenizing each organ aseptically in 1.0 ml of 7H9
broth in a Ten Broeck glass grinder. At least four serial 10-fold
dilutions of the homogenates were plated onto quadrants of selective
7H10 agar plates, and each dilution was plated in duplicate. Colony
counts were recorded after incubation at 37°C in a CO2
incubator for 5 weeks. For organs from which no colonies were obtained
by the quantitative plate method, the remaining suspension (0.8 ml) was
inoculated into bottles containing 5 ml of selective 7H9 liquid medium.
After incubation for 5 weeks, the 7H9 medium was subcultivated onto
slants of Löwenstein-Jensen medium, which were incubated for 6 weeks. Organs were considered sterilized if no tubercle bacilli grew
during any of these steps.
Pharmacokinetics.
Pairs of mice were bled immediately prior
to (t = 0) and at five time points following
(t = 15, 30, 60, 120, and 240 min) administration of
various doses of moxifloxacin by gavage. Serum was prepared and frozen
at Statistical analysis.
Student's t test was used
to compare paired data, and a P value of less than 5%
denoted statistical significance. No adjustments were made from
multiple comparisons.
In vitro activity of moxifloxacin against M. tuberculosis CSU93.
To determine the MIC of moxifloxacin
against M. tuberculosis CSU93, we added moxifloxacin at
concentrations ranging from 0.06 to 2.0 µg/ml to BACTEC bottles into
which 105 CFU of M. tuberculosis CSU93 was
inoculated. The BACTEC bottles were then incubated at 37°C for 4 to 7 days. Data were obtained as a growth index, which is a measure of the
14CO2 liberated by M. tuberculosis during the decarboxylation of 14C-labeled
palmitate in the medium and is directly proportional to the amount of
active growth in the vial. In vitro-grown M. tuberculosis CSU93 was susceptible to moxifloxacin, and the
MIC was found to be 0.25 µg/ml by this method.
In vivo activity of moxifloxacin in mice infected with
M. tuberculosis.
Two long-term experimental protocols
were evaluated: the first was low-titer infection with high-dose
moxifloxacin treatment, and the second was high-titer infection with
low-dose moxifloxacin treatment.
(i) Low-titer infection with high-dose moxifloxacin.
In the
first experiment, mice were infected with 5.9 × 105
CFU of M. tuberculosis CSU93. One week after
inoculation, the infected mice were divided into four groups and
treatment was initiated. Groups of 16 mice each were treated with
moxifloxacin alone (100 mg/kg of body weight), INH alone (25 mg/kg), a
combination of moxifloxacin and INH at the same doses as with the
monotherapy, or water (control). Eight mice per group were euthanized
at 4 and 8 weeks of treatment.
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Moxifloxacin (BAY12-8039), a New
8-Methoxyquinolone, Is Active in a Mouse Model of
Tuberculosis
ABSTRACT
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
70°C until use. Serum moxifloxacin levels were measured by
high-performance liquid chromatography. The concentrations were
calculated by using drug standards dissolved in human serum.
RESULTS
Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
TABLE 1.
Spleen weights of mice after treatment with moxifloxacin,
INH, or moxifloxacin plus INH following inoculation
of M. tuberculosis
TABLE 2.
CFU counts in organ homogenates after treatment with
moxifloxacin, INH, or moxifloxacin plus INH following inoculation
of M. tuberculosis
(ii) High-titer infection with low-dose moxifloxacin. In the second experiment, we challenged mice with a larger inoculum of the M. tuberculosis CSU93 strain and treated them with a lower dose of moxifloxacin. Mice received 1.0 × 107 CFU of M. tuberculosis; on the day following infection they were randomly divided into three groups of 16 mice and started on daily treatment with moxifloxacin (20 mg/kg), moxifloxacin (20 mg/kg) plus INH (25 mg/kg), or water (control). After treatment for 3 weeks, eight mice from each group were euthanized for measurement of CFU counts in the spleens and lungs and for pathological assessment. The remaining mice were euthanized at 7 weeks of treatment.
Mice treated with moxifloxacin or with moxifloxacin plus INH gained weight, whereas the body weight curve for the control group declined beginning 3 weeks after treatment. Five mice in the control group died of tuberculosis during the 7-week experiment, while no mice in either group that received drug(s) died (Table 3 and Fig. 1). The lungs from the dead mice were hard and inelastic, and their surface areas had turned white, consistent with overwhelming tuberculosis. Among the survivors examined at 7 weeks, nodular lesions measuring 1 to 3 mm in diameter were observed in all of the untreated mice. Similar lesions were observed in some mice receiving low-dose moxifloxacin but not in those receiving the combination of low-dose moxifloxacin plus INH. As shown in Table 3, at 3 weeks of treatment, the log10 CFU counts in the lungs and spleens for the moxifloxacin-treated mice were significantly lower (P < 0.001) than those for the control group. The combination of moxifloxacin and INH was even more effective in reducing bacillary counts. Whereas this combination reduced the bacillary load in both the lungs and spleens at 7 weeks of treatment compared to that at 3 weeks, we found no difference between the moxifloxacin monotherapy group and the control group in the log10 CFU counts in the lungs and spleens at 7 weeks. As may be seen in Table 3, moxifloxacin monotherapy prevented the expansion of bacillary load between weeks 3 and 7, whereas there was an apparent reduction in counts within the control group. Because only 50% (four of eight mice) of the mice in the control group survived to week 7, it is likely that death of the most heavily infected control mice resulted in a falsely low mean bacillary load in this group at week 7.
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Serum moxifloxacin concentrations.
Serum drug
concentration-time profiles and pharmacokinetic parametric values of
moxifloxacin after a single oral administration in mice are shown in
Table 4. The parameters for moxifloxacin derived from this study are shown with previously published values for
ofloxacin and sparfloxacin. The values for maximum serum drug concentration (Cmax) of moxifloxacin were
similar to those of sparfloxacin and lower than those reported
for equivalent doses of ofloxacin. Dose dependency was investigated
with Cmax values of moxifloxacin. When the MIC
of moxifloxacin for the CSU93 strain determined in this study (0.25 µg/ml) was used, the Cmax/MIC ratios were 8.0, 13.6, and 30.0, respectively, for moxifloxacin at the doses of 25, 50, and 100 mg/kg. As shown in Table 4, the values of the time to
Cmax (Tmax) and the
terminal elimination half-life (t1/2) of
moxifloxacin were similar to those of ofloxacin, although the area
under the concentration-time curve (AUC) was not as great. The AUC
values of moxifloxacin showed direct proportionality with dose.
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Development of M. tuberculosis resistance to moxifloxacin. Mouse-passaged bacilli were isolated from the lungs of animals treated with a low dose (20 mg/kg) of moxifloxacin as monotherapy for 7 weeks in experiment 2 (high-titer infection). Homogenates were amplified by liquid subculture for 1 week to obtain a sufficient inoculum of M. tuberculosis. These bacteria were then analyzed for moxifloxacin susceptibility by the BACTEC method. As may be seen in Fig. 2, both moxifloxacin-exposed and untreated samples retained susceptibility to the drug at concentration of 0.25 µg/ml. Since analysis of these samples revealed a mean titer of 2.5 × 106 CFU in the lungs of these mice, this observation suggests that 7 weeks of low-dose (20 mg/kg) moxifloxacin monotherapy does not produce an appreciable subpopulation of quinolone-resistant bacteria.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and methods
Results
Discussion
References
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Our results clearly indicate that moxifloxacin is active against M. tuberculosis infection in mice. In this study, we used a highly virulent, recently isolated clinical strain of M. tuberculosis (CSU93) which was obtained from the index case of a large tuberculosis outbreak in a small, rural community (25). The in vivo growth rate of this strain in mice has been reported to vastly exceed that of the Erdman strain following aerosol administration. Our intravenously infected mouse model also showed that CSU93 is a virulent strain as demonstrated by the deaths and rising CFU counts, described above, in untreated animals.
In our study, CSU93 was shown to be susceptible to moxifloxacin, and the MIC was 0.25 µg/ml. This agrees well with the results of another study in which the in vitro activity of moxifloxacin against several M. tuberculosis isolates was analyzed and the MIC was found to range from 0.12 to 0.5 µg/ml (26). Based on these results, the MICs for moxifloxacin against M. tuberculosis are below those for ofloxacin and ciprofloxacin (22, 23).
Moxifloxacin given to mice at 100 mg/kg per day exerted a potent therapeutic effect in reducing the bacillary population in the lungs and spleens and in decreasing the spleen weights following infection with 5.9 × 105 CFU per animal. The drug's activity was comparable to that seen with INH used concurrently in the same animal model. Furthermore, a combination of moxifloxacin and INH was highly effective in reducing M. tuberculosis loads and in sterilizing the lungs, indicating that moxifloxacin may prove useful for combination therapy of active tuberculosis. Moreover, the in vivo bactericidal activity of moxifloxacin alone at 100-mg/kg dosing was sufficiently potent to eradicate M. tuberculosis from the lungs of most mice at 8 weeks, which suggests that moxifloxacin monotherapy may be effective in certain clinical applications, such as for secondary prevention in individuals with latent tuberculosis.
To assess the limits of moxifloxacin's effectiveness, we conducted a high-titer infection, low-dose therapy experiment with the mouse model. Following high-dose infection with M. tuberculosis (1.0 × 107 CFU per animal), the survival rate for untreated mice was 50%, contrasted with 100% for those receiving moxifloxacin alone (20 mg/kg per day) or moxifloxacin plus INH (20 mg/kg and 25 mg/kg, respectively, per day). Additionally, at 3 weeks of treatment, the CFU counts in the lungs and spleens for the moxifloxacin group were significantly lower than those for the control group, suggesting potent early bactericidal activity for this quinolone. In view of our pharmacokinetic analysis, which showed low serum moxifloxacin levels following 20-mg/kg dosing, the survival benefit observed in mice treated with low-dose therapy indicates significant in vivo potency of this drug.
The quinolones exert concentration-dependent killing, and the Cmax/MIC ratio has been shown to be a pharmacodynamic correlate of efficacy (3, 14). In the neutropenic rat model of Pseudomonas aeruginosa sepsis, the serum peak concentration/MIC ratio was linked to survival, particularly when high ratios (20:1) were obtained (3). These findings suggest that the clinical utility of newer quinolones will depend on their ability to attain high Cmax/MIC ratios (10:1 to 20:1) for clinically important pathogens. When 100 mg of moxifloxacin per kg was administered to mice, the Cmax/MIC ratio (30.0) exceeded the target level described above.
Our mouse pharmacokinetic analysis showed that the t1/2 and the Tmax of moxifloxacin in mice were similar to those of ofloxacin and shorter than those of sparfloxacin. The Cmax of moxifloxacin at 100-mg/kg dosing was considerably lower than that of ofloxacin and as high as that of sparfloxacin (9). The drug half-life for quinolone antimicrobial agents is known to be much shorter in small animals than in humans (15). In fact, the ranges of t1/2 and the Tmax for moxifloxacin in humans were 11.4 to 14.0 and 1.5 to 2.5, respectively, suggesting that daily dosing with moxifloxacin may be appropriate in humans (20, 21). Another concern with the use of quinolones in antituberculosis treatment has been the development of mycobacterial resistance. However, in this study low-dose (20 mg/kg) moxifloxacin monotherapy for 7 weeks did not lead to the development of a detectable subpopulation of quinolone-resistant organisms. It may be that the combination of potent early bactericidal activity and prolonged half-life in serum limits the rapid accumulation of resistance mutations during moxifloxacin therapy. Also, studies of the rate of resistance to moxifloxacin in larger animals will be useful, in view of the relatively small bacterial burden of M. tuberculosis in mice.
In conclusion, moxifloxacin was bactericidal and sterilizing in mice infected with a highly virulent human isolate of M. tuberculosis. A combination of moxifloxacin and INH was also highly effective, suggesting that this new quinolone may be useful in combination therapy for tuberculosis. Further studies to assess the in vivo activity of moxifloxacin against other strains, including multiple-drug-resistant M. tuberculosis, or against other mycobacterial infections, and to evaluate moxifloxacin in combination with standard agents for the treatment of drug-susceptible tuberculosis will be of great value.
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ACKNOWLEDGMENTS |
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This work was supported in part by a grant from the Bayer Corporation.
We are grateful to Vipin Agarwal for measurements of serum levels of moxifloxacin and to Barbara Painter for helpful advice and for reviewing this manuscript. We thank Ping Chen, Nikki Parrish, and Caryn Good for their skillful technical support and valuable advice and Jennifer Doetsch for assistance in the preparation of the manuscript.
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ADDENDUM |
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Similar results documenting the effectiveness of moxifloxacin in a slightly different mouse model of tuberculosis have recently been published by Ji et al. (9a).
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FOOTNOTES |
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* Corresponding author. Mailing address: Center for Tuberculosis Research, Johns Hopkins School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205-2179. Phone: (410) 955-3507. Fax: (410) 614-8173. E-mail: wbishai{at}jhsph.edu.
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Abstract
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Materials and methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, January 1999, p. 85-89, Vol. 43, No. 1
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