Journal of Antimicrobial Chemotherapy (1999) 44, 393-395
© 1999 The British Society for Antimicrobial Chemotherapy
Brief report |
Activity of moxifloxacin against mycobacteria
Department of Medical Microbiology, Royal Free and University Medical School, Rowland Hill St, London NW3 2PF, UK
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Abstract |
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Moxifloxacin is an 8-methoxyquinolone compound with activity against a wide range of bacteria. We tested its activity in comparison with four other quinolones and isoniazid against clinical isolates of mycobacteria. It proved to be the most active of the quinolones tested against Mycobacterium tuberculosis (MIC90 0.25 mg/L), Mycobacterium avium-intracellulare (MIC90 1.0 mg/L), Mycobacterium kansasii (MIC90 0.06 mg/L) and Mycobacterium fortuitum (MIC90 1 mg/L). These data indicate that moxifloxacin merits further study as an antimycobacterial agent.
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Introduction |
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The incidence of tuberculosis is increasing worldwide and recent reports of multi-drug-resistant tuberculosis (MDR-TB) have stimulated the search for new anti-tuberculosis agents.1 Many first line drugs give rise to serious adverse events especially in patients infected with HIV, and no new anti-tuberculosis agents have been introduced since rifampicin first became available in the 1960s. Consequently there has been considerable interest in the 4-fluoroquinolones which have been shown to have useful activity against Mycobacterium tuberculosis and other mycobacteria.
Many in-vitro studies have been performed to test these compounds against mycobacteria; several have useful activity against M. tuberculosisalthough their activity against non-tuberculosis mycobacteria is more variable. These studies have been reviewed elsewhere.2,3
Moxifloxacin is an 8-methoxyquinolone which has been shown to have activity against a wide range of bacterial pathogens.4 This agent has been studied in clinical trials for the management of respiratory infections. We tested the activity of moxifloxacin, four other quinolones and isoniazid against a battery of M. tuberculosis and non-tuberculosis mycobacteria to assess its potential usefulness in the management of these infections.
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Materials and methods |
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Bacterial isolates
All bacteria were isolates cultured from specimens submitted to the Academic Department of Microbiology of the Royal Free Hospital, London, UK for investigation of mycobacterial disease. The specimens were cultivated on Lowenstein–Jensen (LJ) medium incorporating pyruvate or glycerol. M. tuberculosis was identified on the basis of microscopic morphology, failure to grow on medium containing para-nitroaminobenzoic acid, and by nitrate and Tween reaction. The Mycobacterium Reference Laboratory of the PHLS at Dulwich, UK performed species identification of non-tuberculosis isolates by conventional biochemical techniques.5 The isolates tested were M. tuberculosis (19), Mycobacterium avium-intracellulare (12), Mycobacterium kansasii (10), Mycobacterium fortuitum (7) and Mycobacterium chelonae (1).
Source of drugs
Antibiotic preparations used in this study were obtained as pure substance from their manufacturers: ciprofloxacin, moxifloxacin (Bayer, Newbury, UK), ofloxacin, levofloxacin (Hoechst Marion Roussel, Denham, UK), sparfloxacin (Rhone Poulenc Rorer, West Malling, UK) and isoniazid (Sigma, Poole, UK).
Minimal inhibitory concentration (MIC) determination
The antibiotic concentration ranges tested were as follows: for M. tuberculosis, ciprofloxacin 0.25–1 mg/L, levofloxacin 0.12–0.5 mg/L, sparfloxacin 0.03–0.12 mg/L and moxifloxacin 0.12–0.5 mg/L; for M. kansasii similar ranges were used except for moxifloxacin (0.06–0.5 mg/L); for M. avium-intracellulare, ciprofloxacin and levofloxacin 1–8 mg/L, sparfloxacin and moxifloxacin 0.25–2 mg/L. For the rapid growers the range tested for all drugs was 0.06–16 mg/L.
BACTEC 460-TB method. This method was used for MIC determinations for M. kansasii and M. avium-intracellulare. Bacteria grown previously on LJ media were sub-cultured on to Middlebrook 7H9 broth until a growth of 0.5 to 1 MacFarland standard was obtained. The broth was then diluted with 0.02% Tween, 0.1% albumin diluent 1:20 for M. kansasii to provide an inoculum of c. 5 x 104 cfu and 1:100 for M. avium to produce an inoculum of c. 104 cfu. These inocula were added to the drug-containing vials. The drug free control was inoculated with a 1:100 dilution of the inoculum used to inoculate the antibiotic-containing vials.6 The MIC was defined as the lowest concentration showing a daily change in growth index through the 1% control.7
The proportion method. This method was used for MIC determinations for M. tuberculosis. Bacteria from LJ slants were subcultured into Middlebrook 7H9 broth (Difco, Oxford, UK) to provide an inoculum. Once growth had reached 0.5 to 1 MacFarland, the broth was diluted 1:100 to provide an inoculum of c. 104 cfu for inoculation on to drug-containing solid Middlebrook 7H10 agar media (Difco). It was diluted 1:10,000 in 0.02% Tween 0.1% albumin diluent for inoculation on to antibiotic free media. Plates were incubated for 2–3 weeks. The MIC was defined as the lowest concentration showing growth <1% of that of the initial inoculum on the antibiotic free plate.
Agar incorporation MIC. This method was used for MIC determination for M. fortuitum and M. chelonae. Agar incorporation MICs were determined on Müller–Hinton agar (Unipath, Basingstoke, UK) supplemented with 10% OADC (Difco). An inoculum of 104 cfu/spot was diluted 1:10 from a 0.5 MacFarland culture and delivered by a Denley multi-point inoculator. Plates were incubated at 30°C for 48 h. The MIC was defined as the lowest concentration of drug to inhibit macroscopically visible colonies.
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Results |
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Activity against M. tuberculosis
Against M. tuberculosis, moxifloxacin was more active than ciprofloxacin, levofloxacin and slightly superior to sparfloxacin (Table). The MICs of ciprofloxacin and levofloxacin for M. avium-intracellulare were variable: both sparfloxacin and moxifloxacin showed consistently good activity against this organism. Moxifloxacin was the most active of the quinolones tested against isolates of M. kansasii with an MIC90 of 0.25. Of the rapidly growing mycobacteria tested, a single strain of M. chelonae was highly resistant to all of the fluoroquinolones tested. In contrast only ofloxacin was poorly active against M. fortuitum. Moxifloxacin exhibited the greatest activity against these isolates.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussionReferences |
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Fluoroquinolones are a group of agents that might provide suitable treatment for mycobacterial diseases including tuberculosis. New agents are required because of the worldwide rise in the number of cases, and the spread of resistance to existing agents. Patients who are HIV-seropositive frequently are unable to tolerate standard agents and so quinolones are sometimes used as part of the regimen in these cases.2
Moxifloxacin was the most active of the fluoroquinolones tested against M. tuberculosis, having slightly better activity than sparfloxacin. Previous clinical studies have indicated that a ciprofloxacin-containing regimen lacked sterilizing activity in comparison with a standard protocol,8 but the MICs of moxifloxacin were at least four-fold lower than those of ciprofloxacin. Ciprofloxacin has been shown to have early bactericidal activity against M. tuberculosis (a signifcant fall in cfu in the first 48 h of therapy),9 a characteristic shared only with isoniazid.2,10 The activity demonstrated in the present study suggests that moxifloxacin may also have this characteristic. The evidence of enhanced activity compared with other quinolones and favourable pharmacokinetics of moxifloxacin suggest that it may have a role in anti-tuberculosis therapy in the future.11
The superior activity of moxifloxacin in comparison with other quinolones was also found for the other slow-growing pathogens, M. avium-intracellulare and M. kansasii, as well as for the rapidly growing M. fortuitum. A single strain of M. chelonae was resistant to all of the agents tested. Other studies of moxifloxacin have shown similar activity against mycobacterial species.12
Of particular note is the activity against M. avium-intracellulare. This organism is often difficult to treat and moxifloxacin has markedly better in-vitro activity than the other available agents, ciprofloxacin and levofloxacin. These data encourage further in-vitro and clinical studies to investigate the usefulness of moxifloxacin in the treatment of mycobacterial infections.
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Acknowledgments |
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The authors are grateful to Professor J. M. T. Hamilton-Miller for his critical review of this manuscript. This work was performed with the financial assistance of Bayer AG.
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Notes |
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* Corresponding author. Tel: +44-171-794-0500; Fax: +44-171-794-0433; E-mail: stepheng{at}rfhsm.ac.uk
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References |
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1 . Raviglione, M. C., Snider, D. E. & Kochi, A. (1995). Global epidemiology of tuberculosis: morbidity and mortality of a worldwide epidemic. Journal of the American Medical Association 273, 220–6.
2 . Gillespie, S. H. & Kennedy, N. (1998). Fluoroquinolones; a new treatment for tuberculosis? International Journal of Tuberculosis and Lung Diseases 2, 265–71.
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7 . Hawkins, J. E., Wallace, R. J. & Brown, B. A. (1992). Antibacterial susceptibility tests: Mycobacteria. In Manual of Clinical Microbiology, 5th edn (Balows, A., Hansler, W. J., Herrmann, K., Isenberg, H. D. & Shadomy, H. J., Eds), pp. 1138–52. American Society for Microbiology, Washington, DC.
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12 . Gross, W. M., Vadney, F. S., Ladutko, L., Bonato, D. A., Campbell, S. I. (1997). In vitro activity of BAY 12-8039, a new 8-methoxyquinolone, against mycobacteria. In Program and Abstracts of the Thirty-Seventh Interscience Congress on Antimicrobial Agents and Chemotherapy, Toronto, 1997. Abstract F-144. p. 170. American Society for Microbiology, Washington, DC.
Received 5 December 1997; returned 21 January 1998; revised 11 February 1999; accepted 26 April 1999
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