Activity of Quinolones against Mycobacteria

Abstract

The fluoroquinolones have been shown to be highly active in vitro against many mycobacterial species, including most strains of Mycobacterium tuberculosis and M. fortuitum, and some strains of M. kansasii, M. avium-intracellulare (MAI) complex and M. leprae. Ciprofloxacin, ofloxacin and sparfloxacin are the best studied of this class of drugs to date, and they are among the most active of these against M. tuberculosis and other mycobacteria. The use of ofloxacin in the treatment of patients with multidrug-resistant pulmonary tuberculosis has resulted in the selection of quinolone-resistant mutants in a few patients. Many strains of MAI, however, are resistant to fluoroquinolones, and structure-activity relationship studies have been undertaken to identify the moieties associated with activity and inactivity. The most important features determining activity against MAI were found to be a cyclopropyl ring at the N1 position, fluorine atoms at positions C6 and C8, and a C7 heterocyclic substituent. On the basis of these structural requirements, a series of compounds were tested, and many did indeed show good activity against MAI in vitro. Application of these data to macrophage and animal models is in progress. Clinical evaluation of some of these new fluoroquinolones is also being undertaken in multidrug-resistant tuberculosis and MAI and M. leprae infections. Although the development of resistance and the influence of host factors may limit their use, they have considerable potential if prudently used.