Nathally Claudiane de Souza Santos1, Regiane Bertin de Lima Scodro2, Aryadne Larissa de Almeida3, Vanessa Pietrowski Baldin3, Sandra Sayuri Nakamura de Vasconcelos3, Vera Lucia Dias Siqueira4, Katiany Rizzieri Caleffi-Ferracioli4, Paula Aline Zanetti Campanerut-Sá5, Rosilene Fressatti Cardoso6. 1. Programa de Pós-graduação em Biociências e Fisiopatologia, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil. Electronic address: nathallyclaudiane@gmail.com. 2. Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil; Programa de Pós-graduação em Ciências da Saúde, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil. 3. Programa de Pós-graduação em Biociências e Fisiopatologia, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil. 4. Programa de Pós-graduação em Biociências e Fisiopatologia, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil; Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil. 5. Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil. 6. Programa de Pós-graduação em Biociências e Fisiopatologia, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil; Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil; Programa de Pós-graduação em Ciências da Saúde, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, Maringá, Paraná, Brazil.
Abstract
SETTING: The increase of multidrug and extensively drug resistant Mycobacterium tuberculosis strains turns the search for new tuberculosis (TB) treatment options of paramount importance. OBJECTIVE: In this sense, the present study evaluates the in vitro activity of isoniazid (INH)/rifampicin (RIF)/levofloxacin (LVX) and INH/RIF/linezolid (LNZ) combinations in resistant M. tuberculosis. DESIGN: The activities of the combinations were evaluated with M. tuberculosis H37Rv, susceptible and 10 resistant clinical isolates by three-dimensional checkerboard. LVX and LNZ were used as the third drug at fixed ½ and ¼ minimum inhibitory concentration (MIC). INH and RIF were tested at concentrations ranging from 0.0009 μg/mL to 50 μg/mL and 0.0009 μg/mL to 800 μg/mL, respectively. The combinatorial effects were determined by the Fractional Inhibitory Concentration Index (FICI). FICI values ≤ 0.75, 0.75-4 and ≥4 were considered as synergism, indifferent and antagonism, respectively. RESULTS: MIC ranged from 0.03 - 6.25 μg/mL for INH, 0.008-100 μg/mL for RIF, 0.12-0.25 μg/mL for LVX and 0.25-0.5 μg/mL for LNZ in the H37Rv and all clinical isolates. INH/RIF/LVX and INH/RIF/LNZ synergisms were observed in 40 and 50% of the resistant M. tuberculosis clinical isolates and better observed for INH and RIF combined to LVX or LNZ at ¼ MIC. CONCLUSION: The present study calls attention for the potential use of INH/RIF/LVX and INH/RIF/LNZ combinations in the treatment of resistant TB.
SETTING: The increase of multidrug and extensively drug resistant Mycobacterium tuberculosis strains turns the search for new tuberculosis (TB) treatment options of paramount importance. OBJECTIVE: In this sense, the present study evaluates the in vitro activity of isoniazid (INH)/rifampicin (RIF)/levofloxacin (LVX) and INH/RIF/linezolid (LNZ) combinations in resistant M. tuberculosis. DESIGN: The activities of the combinations were evaluated with M. tuberculosis H37Rv, susceptible and 10 resistant clinical isolates by three-dimensional checkerboard. LVX and LNZ were used as the third drug at fixed ½ and ¼ minimum inhibitory concentration (MIC). INH and RIF were tested at concentrations ranging from 0.0009 μg/mL to 50 μg/mL and 0.0009 μg/mL to 800 μg/mL, respectively. The combinatorial effects were determined by the Fractional Inhibitory Concentration Index (FICI). FICI values ≤ 0.75, 0.75-4 and ≥4 were considered as synergism, indifferent and antagonism, respectively. RESULTS: MIC ranged from 0.03 - 6.25 μg/mL for INH, 0.008-100 μg/mL for RIF, 0.12-0.25 μg/mL for LVX and 0.25-0.5 μg/mL for LNZ in the H37Rv and all clinical isolates. INH/RIF/LVX and INH/RIF/LNZ synergisms were observed in 40 and 50% of the resistant M. tuberculosis clinical isolates and better observed for INH and RIF combined to LVX or LNZ at ¼ MIC. CONCLUSION: The present study calls attention for the potential use of INH/RIF/LVX and INH/RIF/LNZ combinations in the treatment of resistant TB.