Fusidic acid is highly active against extracellular and intracellular Mycobacterium leprae

The susceptibilities of 13 isolates of Coxiella burnetii to fusidic acid and ceftriaxone were determined by use of the recently described shell vial assay (D. Raoult, H. Torres, and M. Drancourt, Antimicrob. Agents Chemother, 35:2070-2077, 1991). At a concentration of 4 micrograms/ml, ceftriaxone was bacteriostatic for four isolates and slowed the multiplication of the other nine. Fusidic acid at a concentration of 2 micrograms/ml was bacteriostatic for six isolates and slowed the multiplication of three others. These results show that these compounds could be effective in the phagolysosome of C. burnetii-infected cells.

Section: Discussionmentioning

confidence: 96%

mentioning

confidence: 99%

In vitro activities of ceftriaxone and fusidic acid against 13 isolates of Coxiella burnetii, determined using the shell vial assay

Torres

Raoult

1993

“…To confirm that PA-824 might reasonably be expected to have an effect on lipid catabolism as measured by radiorespirometry, we also confirmed the activity of PA-824 on M. tuberculosis by using radiorespirometry as a measure of viability (BACTEC). The radiorespirometric method has been used extensively to evaluate the in vitro activities of various antileprosy compounds, including macrolides (11), fluoroquinolones (13), phenazines (12), and fusidic acid (10).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium leprae Is Naturally Resistant to PA-824

Manjunatha

Lahiri

Randhawa

et al. 2006

Leprosy responds very slowly to the current multidrug therapy, and hence there is a need for novel drugs with potent bactericidal activity. PA-824 is a 4-nitroimidazo-oxazine that is currently undergoing phase I clinical trials for the treatment of tuberculosis. The activity of PA-824 against Mycobacterium leprae was tested and compared with that of rifampin in axenic cultures, macrophages, and two different animal models. Our results conclusively demonstrate that PA-824 has no effect on the viability of M. leprae in all three models, consistent with the lack of the nitroimidazo-oxazine-specific nitroreductase, encoded by Rv3547 in the M. leprae genome, which is essential for activation of this molecule.Mycobacterium leprae is one of the important pathogens of the genus Mycobacterium, since it is responsible for causing leprosy in humans. Leprosy is caused by a chronic granulomatous infection of the skin and peripheral nerves by bacteria (26). The damage to peripheral nerves results in sensory and motor impairment, leading to deformities and disability. Currently, leprosy is treated with multidrug therapy (MDT) (27). Paucibacillary leprosy patients are treated with dapsone and rifampin for 6 months, and those with multibacillary disease are treated with a combination of dapsone, clofazimine, and rifampin for 12 to 24 months. Despite the success of MDT regimens, newer regimens are required to shorten the duration of chemotherapy and to reduce the relapse rates in multibacillary leprosy cases (4).PA-824 is a 4-nitroimidazo-oxazine compound active against Mycobacterium tuberculosis that is effective against both actively replicating and aerobically growing M. tuberculosis and oxygen-limited, nonreplicating, persistent M. tuberculosis (17,24). Thus, PA-824 is an important lead compound with the potential for reducing the duration of antitubercular chemotherapy. Recently, the Global Alliance for TB Drug Development has initiated phase I clinical trials with PA-824 (www .tballiance.org).PA-824 has a unique spectrum of antibacterial activity. PA-824 is highly active against the M. tuberculosis complex (consisting of M. tuberculosis, Mycobacterium bovis, M. bovis BCG, Mycobacterium africanum, and Mycobacterium microti) but has poor or no activity against mycobacteria outside the M. tuberculosis complex (Mycobacterium avium, Mycobacterium smegmatis, Mycobacterium chelonae, and Mycobacterium fortuitum [24] and Mycobacterium ulcerans [15]). Interestingly, PA-824 is effective against Helicobacter pylori, Clostridium difficile, and a few other microaerophilic and anaerobic bacteria that are distantly related to mycobacteria (1); however, it has no activity against closely related actinomycetes like Nocardia spp. and Streptomyces spp. (U. H. Manjunatha and C. E. Barry, unpublished results). As part of our program to understand the mechanism of action of PA-824 and in view of the loss of a significant amount of genetic information from the leprosy bacillus (7), we sought to determine the susceptibility of M. leprae to PA-824. ...

“…Fusidic acid is active against Mycobacterium leprae both in axenic medium and in macrophage culture as determined in the BACTEC 460 system (50% inhibition at 1.25 to 2.5 ,ug/ml) (9). An earlier attempt to detect antileprosy activity of fusidic acid in the mouse footpad was unsuccessful (7), possibly because of poor absorption of this compound in mice (14).…”

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confidence: 99%

Clinical trial of fusidic acid for lepromatous leprosy

Franzblau

Chan

Garcia-Ignacio

et al. 1994

Self Cite

Fusidic acid was assessed for antileprosy activity in nine lepromatous leprosy patients. Patients received fusidic acid at either 500 mg/day for 12 weeks or 750 mg/day for 4 weeks followed by 500 mg/day for 8 weeks. All patients showed time-dependent clinical improvement and decreases in bacillary morphological index, radiorespirometric activity and PCR signal, and in serum phenolic glycolipid I. Fusidic acid appears to be a weakly bactericidal antileprosy agent which may have a role in the multidrug treatment of leprosy pending an evaluation of lepra-reaction-suppressive activity. 64 ,ug/ml (11, 18, 23) and, when combined with ethambutol, against some Mycobacterium avium complex strains (18).Fusidic acid is active against Mycobacterium leprae both in axenic medium and in macrophage culture as determined in the BACTEC 460 system (50% inhibition at 1.25 to 2.5 ,ug/ml) (9). An earlier attempt to detect antileprosy activity of fusidic acid in the mouse footpad was unsuccessful (7), possibly because of poor absorption of this compound in mice (14).On the basis of the in vitro activity against M. leprae and human pharmacokinetic properties, a clinical trial of filmcoated sodium fusidate (Fucidin; Leo Pharmaceutical) was conducted with lepromatous leprosy patients. In addition to clinical response, morphological index (MI), and mouse footpad infectivity, patient response was also monitored by measurement of serum phenolic glycolipid I antigen as well as radiorespirometry (10) The patients were hospitalized and received either (i) 500 mg of fusidic acid daily for 8 weeks (patients 1 to 5) or (ii) 750 mg of fusidic acid daily for 4 weeks followed by 500 mg daily for 4 weeks (patients 6 to 9). For all patients, this treatment was followed by an additional 4 weeks of administration of 500 mg of fusidic acid daily as outpatients in order to evaluate the clinical response further.The degree of clinical improvement was assessed according to previously described criteria (3). Serum and 6-mm skin punch biopsy samples were collected just prior to initiation of treatment and at 2-week intervals for 8 weeks. Part of each biopsy sample was processed for mouse footpad assay, radiorespirometry, and MI. The remaining portion was processed separately for PCR. The BI was determined from skin slit smears from at least six sites.The procedure of Cho et al. (6) for measuring phenolic glycolipid I antigen levels was followed. Scoring was based on the relative intensity of color development from the reaction of peroxidase with 4-chloro-1-naphthol.The infectivity for mice of 5, 50, 500, or 5,000 acid-fast bacilli (AFB) from skin biopsy homogenates was determined as previously described (3