1 Department of Medicine, Veterans Affairs Medical Center, 800 Irving Avenue, Syracuse, NY 13210; 2 Jacobus Pharmaceutical Company Inc., Princeton, NJ, USA
Received 29 October 2002; accepted 9 May 2003
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Abstract |
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Keywords: clarithromycin, chemotherapy, combination therapy, M. kansasii, murine infection model, mycobacteria
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Introduction |
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Materials and methods |
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Each treatment group contained six mice. Treatment began 1 week post-infection, with drugs administered orally by gavage 5 days per week for 4 weeks. The following treatment groups were included: untreated early and late controls, gatifloxacin (100 mg/kg), clarithromycin (200 mg/kg), linezolid (100 mg/kg), gatifloxacin + clarithromycin, clarithromycin + linezolid, gatifloxacin + linezolid, rifampicin (20 mg/kg) and rifampicin + clarithromycin. Bristol-Myers Squibb (Princeton, NJ, USA) provided gatifloxacin, Abbott Laboratories (Abbott Park, IL, USA) clarithromycin, Pharmacia (Kalamazoo, MI, USA) linezolid, and Sigma Chemical Company (St Louis, MO, USA) rifampicin. Broth dilution MICs for M. kansasii 795 were as follows: 0.25, 2, 4 and 0.25 mg/L of gatifloxacin, clarithromycin, linezolid and rifampicin, respectively. Gatifloxacin and clarithromycin were dissolved in ethanol and distilled deionized water (2:8, v/v). Linezolid and rifampicin were dissolved in dimethyl sulfoxide and distilled deionized water (2:8, v/v). Drugs were delivered in 0.2 mL of vehicle. Mice receiving combination therapy were dosed in the mornings and afternoons.
The early control group was euthanized by CO2 inhalation 1 week post-infection. The late control group was euthanized at the end of the 4 week treatment period. Right lungs were harvested, ground in a tissue homogenizer (IdeaWorks Laboratory Devices, Syracuse, NY, USA), and plated onto 7H10 agar supplemented with 10% OADC to determine viable cell counts. The plates were incubated in ambient air at 37°C for 4 weeks prior to counting. Viable cell counts were converted to logarithms and are shown in Table 1.
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A KruskalWallis analysis of variance produced an H value of 44.78 with 9 df, P < 0.001. This implies that there were statistically significant differences between the groups. To determine which group differed from another, the MannWhitney non-parametric test was used.
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Results and discussion |
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In the monotherapy groups, clarithromycin was significantly more active than gatifloxacin (log cfu counts: 5.53 versus 6.51, respectively; P = 0.022) and linezolid (log cfu counts: 5.53 versus 7.04, respectively; P = 0.008) but it was not statistically different from rifampicin (log cfu counts: 5.53 versus 6.33, respectively; P = 0.08). None of the clarithromycin-containing combinations were statistically better than clarithromycin alone (clarithromycin versus clarithromycin + gatifloxacin, log cfu counts: 5.53 versus 5.89 respectively, P = 0.21; clarithromycin versus rifampicin + clarithromycin, log cfu counts: 5.53 versus 5.04, respectively, P = 0.14; clarithromycin versus clarithromycin + linezolid, log cfu counts: 5.53 versus 5.57, respectively, P = 1.00; clarithromycin versus gatifloxacin + linezolid, log cfu counts: 5.53 versus 6.20, respectively, P = 0.21). Clarithromycin was the most active agent when used alone or in combination with the other drugs; it reduced organ viable cell counts by approximately 2 logs. Rifampicin demonstrated activity against M. kansasii reducing the count by approximately 1 log. Gatifloxacin was as active as rifampicin (log cfu counts: 6.51 versus 6.33, respectively; P = 0.65). Linezolid treatment decreased viable cell counts by only one half of 1 log.
All drug combinations performed as well as or better than either component drug alone; therefore, there was no evidence of any in vivo antagonistic drug interactions. The best combination was rifampicin + clarithromycin (log cfu count: 5.04). This combination worked better than rifampicin (log cfu counts: 6.33), gatifloxacin (log cfu counts: 6.51) or linezolid (log cfu counts: 7.04) alone, and was also more active than the gatifloxacin + clarithromycin combination (log cfu counts: 5.89).
These results confirmed the favourable activity of clarithromycin and rifampicin against M. kansasii in mice. It would be of interest to evaluate further the activity of fluoroquinolones such as gatifloxacin against non-tuberculous mycobacteria including M. kansasii. Based on the activities of each of these agents alone, the combination of rifamycin derivatives and fluoroquinolones merits more attention. Additional murine model studies, as well as clinical studies, are necessary to define the most effective and safest way to use clarithromycin in combination to treat infections caused by M. kansasii and other non-tuberculous mycobacteria.
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Acknowledgements |
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Footnotes |
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References |
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2 . Hopewell, P., Cynamon, M., Starke J. et al. (1992). Evaluation of new anti-infective drugs for the treatment of disease caused by Mycobacterium kansasii and other mycobacteria. Clinical Infectious Diseases 15, Suppl. 1, S30712.[ISI][Medline]
3 . Jenkins, P. A., Banks, I., Campbell, I. A. et al. (Research Committee of the British Thoracic Society). (1994). Mycobacterium kansasii pulmonary infection: A prospective study of the results of nine months of treatment with rifampicin and ethambutol. Thorax 49, 4425.[Abstract]
4 . Wallace, R. J., Jr, Glassworth, J., Griffith, D. et al. (1977). Diagnosis and treatment of disease caused by nontuberculous mycobacteria. American Thoracic Society Statement. American Journal of Respiratory and Critical Care Medicine 156, Suppl., S1S25.
5 . Schraufnagel, D. E., Leech, J. A., Nissen Schraufnagel, M. et al. (1984). Short-course chemotherapy for mycobacteriosis kansasii? Canadian Medical Association Journal 130, 348.[Abstract]
6 . Shronts, J. S., Rynearson, T. K. & Wolinsky, E. (1971). Rifampin alone and in combination with other drugs in Mycobacterium kansasii and Mycobacterium intracellulare infections of mice. American Review of Respiratory Disease 104, 72841.[ISI][Medline]
7 . Klemens, S. P. & Cynamon, M. H. (1994). Activities of azithromycin and clarithromycin against nontuberculous mycobacteria in beige mice. Antimicrobial Agents and Chemotherapy 38, 14559.[Abstract]
8 . Dautzenberg, B., Truffot, C., Legris, S. et al. (1991). Activity of clarithromycin against M. avium infection in patients with the acquired immune deficiency syndrome: a controlled clinical trial. American Review of Respiratory Disease 144, 5649.[ISI][Medline]
9 . Fernandes, P. B., Hardy, D. J., McDaniel, D. et al. (1989). In vitro and in vivo activities of clarithromycin against Mycobacterium avium. Antimicrobial Agents and Chemotherapy 33, 161416.[ISI][Medline]
10 . Heifets, L. B., Lindholm-Levy, P. J. & Comstock, R. D. (1992). Clarithromycin minimal inhibitory and bactericidal concentrations against Mycobacterium avium. American Review of Respiratory Diseases 145, 8568.
11
.
Alvirez-Freites, E. J., Carter, J. L. & Cynamon, M. H. (2002). In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy 46, 10225.
12
.
Cynamon, M. H., Klemens, S. P., Sharpe, C. A. et al. (1999). Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrobial Agents and Chemotherapy 43, 118991.