In vitro activity of levofloxacin, singly and in combination with rifamycin analogs, against Mycobacterium leprae

Abstract

The in vitro susceptibility of Mycobacterium leprae to levofloxacin was studied by using two biochemical parameters to measure the metabolic activity of the organism. Levofloxacin consistently exhibited twofold greater bactericidal activity than ofloxacin, with the MIC being 0.75 g/ml. When combined with one of the three rifamycin analogs, synergism was obtained with KRM-1648 and rifabutin but not with rifampin.The frontline drugs against leprosy since 1947 have been either dapsone, clofazimine, or rifampin. In 1981, the World Health Organization recommended the use of multidrug therapy consisting of these three drugs (20), and this has resulted in the reduction of the global prevalence of leprosy by about 57% (17). However, there are still 3.1 million cases of leprosy in the world, and about 600,000 new cases are being detected annually (17). Thus, the research will have to continue to develop new bactericidal drugs and also to formulate new multidrug therapy regimens for the treatment of multibacillary leprosy that will give better results in much shorter time.The use of fluoroquinolones in the treatment of mycobacterial diseases, including tuberculosis, is now well accepted (13,19,21). Grosset and associates (10, 11) have found ofloxacin to be the most active agent against Mycobacterium leprae in both mice and patients with leprosy. They have shown that about 99.99%, or 4 logs, of M. leprae viable on day zero were killed by 22 doses of ofloxacin. Except for rifampin, no other drug thus far tested in humans with leprosy has demonstrated such a degree of bactericidal activity (14). Recently, Tomioka and Saito (18) have reported that use of the combination of ofloxacin and rifampin gave a significant increase in their efficacies. Using an in vitro system (7) and a mouse footpad model (5), we have observed a synergistic effect when ofloxacin was combined with rifabutin but not when it was combined with rifampin.Ofloxacin exists as two optically active isomers because of the asymmetric center at the C-3 of the oxazine ring, and levofloxacin (the optically active L isomer of ofloxacin) has shown high levels of antibacterial activity against a number of bacterial species both in vitro and in mice (9). Recently, Heifets and associates (16) have observed a twofold greater inhibitory activity of levofloxacin over that of ofloxacin against extracellular as well as intracellular tubercle bacilli.The aim of the present study was therefore to evaluate the activity of levofloxacin in comparison with that of ofloxacin against M. leprae in an in vitro system and also to study its synergism when it was combined with rifamycin analogs.Antimicrobial agents. Levofloxacin and ofloxacin were obtained from the R. W. Johnson Pharmaceutical Research Institute (Raritan, N.J.). Stock solutions of levofloxacin and ofloxacin were prepared by first dissolving them in small amounts of 0.1 M NaOH and then diluting those solutions with distilled water to obtain appropriate working solutions. Three rifamycin analogs were tested: rifampin (Sigm...

In-vitro activity of sitafloxacin (DU-6859a), either singly or in combination with rifampin analogs, against Mycobacterium leprae

“…Also, in our previous studies, parallelism between ATP values and [ 3 H]-thymidine uptake values has been demonstrated. 14,16 Thus, it is safe to assume that the increase in metabolic activity of M. leprae observed in the present study is an indication of an increase in the cell numbers in primary cultures.…”

“…14,27 The method for calculating and interpreting the fractional inhibitory concentration (FIC; interaction index) has been described earlier. 16 Sampling for the assays 14 and analysis of data 16 were carried out as described earlier.…”

“…Dhople and co-workers had earlier demonstrated antibacterial activities of ofloxacin 14,15 and levofloxacin 16 against M. leprae. A new fluoroquinolone, sitafloxacin (DU-6859a) had been shown to be more potent against various Grampositive organisms 17 and also mycobacteria, including M. tuberculosis, 18,19 than ofloxacin.…”

In vitro activities of levofloxacin used alone and in combination with first- and second-line antituberculous drugs against Mycobacterium tuberculosis

“…Levofloxacin is the optically active L-isomer of ofloxacin, and the antimicrobial activity of levofloxacin is 8 to 128 times greater than that of the corresponding D-isomer (9). Levofloxacin is about twice as potent as ofloxacin against various microorganisms including M. tuberculosis, a variety of atypical mycobacteria, and M. leprae (5,7,9,15,18,20,34,38,40). At the pharmacokinetic level, both levofloxacin and ofloxacin are characterized by similar absorption rates (7,19,38,40), with a higher intracellular concentration/extracellular concentration ratio for levofloxacin compared with that for ofloxacin in cultured human macrophages (38.44 Ϯ 1.1 versus 27.1 Ϯ 0.8 g/ml, respectively) (18).…”

Tuberculosis treatment unmasking leprosy: management of drug-resistant tuberculosis and leprosy co-infection

“…Tuberculosis treatment unmasking leprosy: management of drug-resistant tuberculosis and leprosy co-infection G. Kama, 1 G. K. L. Huang, 2 M. Taune, 1 R. Arura, 1 L. Morris, 3 B. Kombuk, 1 A. Marome, 4 D. P. O'Brien 2,5…”