SYNERGISTIC ACTIVITIES OF CLARITHROMYCIN AND ANTITUBERCULOUS DRUGS AGAINST MULTIDRUG-RESISTANT MYCOBACTERIUM-TUBERCULOSIS

The rise of multidrug-resistant Mycobacterium tuberculosis has complic ated therapy for tuberculosis and led us to search for a potentially a ctive combination of drugs against these strains. The susceptibilities of 12 strains of multidrug-resistant M. tuberculosis to standard anti tuberculous drugs (isoniazid, rifampin, ethambutol, and pyrazinamide), clarithromycin, and its metabolite, 14-hydroxyclarithromycin, were de termined by use of the BACTEC radiometric method. All strains were res istant to at least two of the antituberculous drugs. Clarithromycin an d 14-hydroxyclarithromycin MICs were in the range indicating resistanc e at greater than or equal to 8.0 mu g/ml for all strains. Combination testing by the BACTEC method was performed with various concentration s of isoniazid, rifampin, and ethambutol, and with clarithromycin/14-h ydroxyclarithromycin at fixed concentrations of 2.0/0.5 mu g/ml, respe ctively. Addition of clarithromycin/14-hydroxyclarithromycin to these antituberculous drug mixtures resulted in a 4- to 32-fold reduction in MICs ofisoniazid, rifampin, and ethambutol and made resistant strains susceptible. Fractional inhibitory concentrations ranged from 0.23 to 0.50 for all strains, suggesting a synergistic interaction between st andard antitubercuIous drugs and clarithromycin/14-hydroxyclarithromyc in. The ability of clarithromycin/14-hydroxyclarithromycin to enhance the activities of isoniazid, ethambutol, and rifampin in vitro suggest s that this combination may be efficacious in the treatment of multidr ug-resistant M. tuberculosis infections.