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Antimicrobial Agents and Chemotherapy, April 2008, p. 1549-1550, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.00148-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

In Vivo Therapeutic Effect of Gatifloxacin on BALB/c Mice Infected with Nocardia brasiliensis

Alejandra Daw-Garza,¹ Oliverio Welsh,¹ Salvador Said-Fernández,³ Hector Gerardo Lozano-Garza,³ Noemi Waksman de Torres,² Norma Cavazos Rocha,² Jorge Ocampo-Candiani,¹ and Lucio Vera-Cabrera^1*

Servicio de Dermatología, Hospital Universitario "José E. González," Monterrey, N.L,¹ Departamento de Química Analítica Facultad de Medicina, UANL, Monterrey, N.L,² Centro de Investigación Biomédica del Noreste, IMSS, Monterrey, N.L., México³

Received 2 February 2008/ Accepted 6 February 2008

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In the present work, we evaluated the effect of gatifloxacin on the evolution of experimental murine infection with Nocardia brasiliensis using linezolid as a control. Gatifloxacin was injected subcutaneously at 100 mg/kg body weight every 8 h for 4 weeks. This compound was equally as efficient as linezolid in reducing the production of lesions.

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Mycetoma is a multietiological subcutaneous infection caused by true fungi and aerobic actinomycetes observed in many tropical and subtropical countries (8). In Mexico, 98% of the total cases are produced by actinomycetes and about 86% are produced by Nocardia brasiliensis (3). The highest cure rates (70%) have been obtained with the use of sulfamethoxazole-trimethoprim. In our dermatology clinic we have added amikacin to the sulfamethoxazole-trimethoprim combination to treat severe cases of mycetoma or those cases involving subjacent organs, obtaining a cure rate of about 95% in a series of 52 patients (7). However, in some cases, the use of these antimicrobials carries the risk of side effects, or we can have the development of bacterial resistance, making necessary the search for new therapeutic alternatives.

Quinolones are a group of antimicrobials with no or poor in vitro activity against Nocardia brasiliensis (2). However, the most recent compounds of this class, such as moxifloxacin, gatifloxacin, and garenoxacin, have been observed to be highly active in vitro against this microorganism (6), exhibiting MICs similar to those presented by linezolid and amikacin, which are active in human infections. Therefore, it is important to confirm the activity of these quinolones in animal infections before using them in human subjects. In the present work, we used a murine animal model to study the activity of one of these quinolones, gatifloxacin, and compared its effectiveness with that of linezolid.

For the animal assays, we utilized Nocardia brasiliensis HUJEG-1, which has been utilized in previous studies (2). The MICs of this strain, determined by the broth microdilution method, are 0.25 µg/ml for gatifloxacin and 0.12 µg/ml for linezolid.

For the determination of the plasma levels of gatifloxacin and linezolid, several doses of these compounds were used. Linezolid was used at 10 mg/kg body weight, 25 mg/kg, and 50 mg/kg, and gatifloxacin at 50 mg/kg, 75 mg/kg, and 100 mg/kg. Eight- to 12-week-old female BALB/c mice were injected subcutaneously with the antimicrobials. For each dose tested, 27 mice were utilized; 24 were injected with the selected dose, and 3 mice were not injected to represent time zero. Next, 500-µl blood samples were taken from the infraorbital sinus of each mouse, which previously had undergone general anesthesia with ethylic ether. The samples were taken from groups of three mice each at the following time intervals: 0 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 10 h. After sample collection, the plastic tubes containing the blood were centrifuged and the plasma was separated and frozen at –70°C. Plasma concentrations were determined by using a previously validated high performance liquid chromatography method (1). For the therapeutic assays, 8- to 12-week-old female BALB/c mice were inoculated with 20 mg of Nocardia brasiliensis in the right hind footpad. Seven days later, the therapeutic assay was started. Groups of 15 mice each were used. One group was injected subcutaneously in the back with 0.1 ml of pyrogen-free saline; the rest were treated with either gatifloxacin at 100 mg/kg or linezolid at 25 mg/kg. All the treatments, including the saline solution, were given subcutaneously on the back three times per day during a 4-week period. The development of lesions in the footpad of the animals was scored by two independent readers as described previously (2). This system classifies the lesions from those animals presenting absolutely no lesions or inflammation as negative or zero and the lesions from animals presenting severe lesions extending above the metatarsal bones as 4+. Differences among the therapeutic groups were analyzed using the analysis of variance test and confirmed with the Dunnet analysis.

Gatifloxacin at 100 mg/kg maintained plasma levels over the MIC of N. brasiliensis HUJEG-1 (0.25 µg/ml) for more than 4 h, reaching a maximum concentration in serum of 18 µg/ml (Fig. 1). Linezolid at 25 mg/kg also kept concentrations above the MIC (0.12 µg/ml) for more than 4 h, with a maximum concentration in serum of 50 µg/ml. Given these results, we decided to use gatifloxacin at 100 mg/kg three times daily, injected subcutaneously, and linezolid also three times per day at 25 mg/kg. In Fig. 2, the effect of gatifloxacin on the development of the lesions is shown. The animals showed a decrease in the number of lesions, comparable to the effect of linezolid. When the results were analyzed with the one-way analysis of variance test, both treatments, either with linezolid or with gatifloxacin, were statistically significant with a P value of 0.001 compared with the group of animals injected with saline. Equal results were obtained when analyzing the mean values with the Dunnet test.

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FIG. 1. Mouse plasma levels of the antimicrobials used in this study. Gatifloxacin (left) was injected subcutaneously at 50 (•), 75 (), and 100 () mg/kg. Linezolid (right) doses utilized were 10 (•), 25 (), and 50 () mg/kg. Each point represents the mean of the measurements from three animals.

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FIG. 2. Effect of saline solution, gatifloxacin, and linezolid on the development of experimental lesions by N. brasiliensis on the mouse footpad. Statistically significant (P < 0.005) differences from the results from the control animals were observed for the groups treated with linezolid and gatifloxacin.

Although quinolones have successfully been used to treat some Nocardia sp. infections (5, 9), they have been of little value for treating N. brasiliensis infections. As mentioned above, we have observed that new quinolones such as garenoxacin, moxifloxacin, and gatifloxacin are quite active in vitro against N. brasiliensis. Based on this premise, we selected one of them, gatifloxacin, to test its in vivo activity, observing an activity comparable to that of linezolid. To our knowledge, our animal model is the only one utilized to study the effect of antimicrobials on actinomycetoma. By using this murine model, we previously reported the activity of linezolid on N. brasiliensis; later, other authors proved its effectivity in treating nocardial subcutaneous human infections (4). The results presented herein show that gatifloxacin has an important in vivo effect on N. brasiliensis, introducing the possibility of using this compound in the future for the treatment of human actinomycetoma infections. Other quinolones with similar MICs, such as moxifloxacin, garenoxacin, or new experimental compounds, may have similar in vivo effects, although this will have to be determined experimentally.

 
This research partially fulfills the requirement for the Doctor of Medicine degree (Facultad de Medicina, Universidad Autónoma de Nuevo León) of the first author (A.D.-G.).

 
* Corresponding author. Mailing address: Servicio de Dermatología, Hospital Universitario, U.A.N.L., Madero y Gonzalitos, Colonia Mitras Centro, C.P. 64460, Monterrey, N.L., México. Phone: 5281 8348 0383. Fax: 5281 8348 44 07. E-mail: luvera_99{at}yahoo.com

Published ahead of print on 19 February 2008.

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Antimicrobial Agents and Chemotherapy, April 2008, p. 1549-1550, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.00148-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Chacon-Moreno, B. E., Welsh, O., Cavazos-Rocha, N., de la Luz Salazar-Cavazos, M., Garza-Lozano, H. G., Said-Fernandez, S., Ocampo-Candiani, J., Vera-Cabrera, L. (2009). Efficacy of Ciprofloxacin and Moxifloxacin against Nocardia brasiliensis In Vitro and in an Experimental Model of Actinomycetoma in BALB/c Mice. Antimicrob. Agents Chemother. 53: 295-297 [Abstract] [Full Text]  

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