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Antimicrobial Agents and Chemotherapy, August 1999, p. 1870-1874, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Mefloquine Is Active In Vitro and In Vivo against Mycobacterium avium Complex

Luiz E. Bermudez,1,* Peter Kolonoski,1 Martin Wu,1 Priscilla A. Aralar,2 Clark B. Inderlied,2 and Lowell S. Young1

Kuzell Institute for Arthritis and Infectious Diseases, San Francisco,1 and Department of Pathology and Laboratory Medicine, Children's Hospital of Los Angeles, University of Southern California, Los Angeles,2 California

Received 16 February 1999/Returned for modification 23 April 1999/Accepted 11 May 1999

Despite the development of several agents, new classes of antimicrobials with activity against the Mycobacterium avium complex (MAC) are needed. Based on a broad screening of compounds, we found that mefloquine has MICs of 8 to 16 µg/ml by the BACTEC system and 16 µg/ml by broth microdilution for five MAC strains tested. An expansion of the screening with broth microdilution to 24 macrolide-susceptible strains and 6 macrolide-resistant strains determined that the MIC for all strains was 16 µg/ml. To determine the intracellular activity of mefloquine, U937 macrophage monolayers infected with MAC strain 101, 100, or 109 (serovars 1, 8, and 4) were treated with mefloquine daily, and the number of intracellular bacteria was quantitated after 4 days. Significant growth inhibition against the three MAC strains at concentrations greater than or equal to 10 µg/ml (P < 0.05) was obtained. Due to the encouraging anti-MAC activity, in vivo efficacy in beige mice infected with MAC 101 was evaluated. Animals were treated with 5, 10, 20, or 40 mg/kg of body weight daily, three times a week, twice a week, or once a week for 4 weeks, and bacteria were quantitated in blood, liver, and spleen. No toxicity was observed with any of the treatment regimens. Mefloquine had borderline bactericidal activity at a dosage of 40 mg/kg daily (100% inhibition compared with a 1-week control), and significant inhibition was obtained at dosages of 40 mg/kg three times a week, as well as 20 mg/kg daily. Mefloquine had no significant effect on bacteremia. A combination of mefloquine and ethambutol showed significantly more activity than did either drug alone in liver, spleen, and blood; the combination was also bactericidal against M. avium. Although safety is a potential concern, mefloquine and related compounds deserve further investigation as anti-MAC therapies.

* Corresponding author. Mailing address: Kuzell Institute, 2200 Webster St., Suite 305, San Francisco, CA 94115. Phone: (415) 561-1734. Fax: (415) 441-8548. E-mail: luizb{at}cooper.cpmc.org.

Antimicrobial Agents and Chemotherapy, August 1999, p. 1870-1874, Vol. 43, No. 8
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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