Activity of rifampicin and linezolid combination in Mycobacterium tuberculosis

Flaviane Granero Maltempe; Katiany Rizzieri Caleffi-Ferracioli; Renata Claro Ribeiro do Amaral; Fernanda de Oliveira Demitto; Vera Lúcia Dias Siqueira; Regiane Bertin de Lima Scodro; Mário Hiroyuki Hirata; Fernando Rogério Pavan; Rosilene Fressatti Cardoso

doi:10.1016/j.tube.2017.02.004

Activity of rifampicin and linezolid combination in Mycobacterium tuberculosis

Tuberculosis (Edinb). 2017 May:104:24-29. doi: 10.1016/j.tube.2017.02.004. Epub 2017 Feb 20.

Authors

Flaviane Granero Maltempe¹, Katiany Rizzieri Caleffi-Ferracioli², Renata Claro Ribeiro do Amaral¹, Fernanda de Oliveira Demitto³, Vera Lúcia Dias Siqueira², Regiane Bertin de Lima Scodro², Mário Hiroyuki Hirata⁴, Fernando Rogério Pavan⁵, Rosilene Fressatti Cardoso⁶

Affiliations

¹ Postgraduation in Bioscience and Physiopathology, State University of Maringá, Avenida Colombo 5790, Maringá, Paraná, 87020-900, Brazil.
² Laboratory of Medical Bacteriology, Laboratory of Teaching and Research in Clinical Analysis (LEPAC), Department of Clinical Analysis and Biomedicine, State University of Maringa, Avenida Colombo 5790, Maringá, Paraná, 87020-900, Brazil.
³ Postgraduation in Health Sciences, State University of Maringá, Avenida Colombo 5790, Maringá, Paraná, 87020-900, Brazil.
⁴ School of Pharmaceutical Sciences, University of São Paulo, São Paulo, 05508-900, Brazil.
⁵ School of Pharmaceutical Sciences, Department of Biological Sciences, Paulista State University, Araraquara, São Paulo, 14800-901, Brazil.
⁶ Laboratory of Medical Bacteriology, Laboratory of Teaching and Research in Clinical Analysis (LEPAC), Department of Clinical Analysis and Biomedicine, State University of Maringa, Avenida Colombo 5790, Maringá, Paraná, 87020-900, Brazil. Electronic address: rfressatticardoso@gmail.com.

PMID: 28454646
DOI: 10.1016/j.tube.2017.02.004

Abstract

Background: Linezolid (LZD) is not commonly used for treating tuberculosis (TB), but in some patients with drug-resistant TB it is being used. However, the in vitro LZD activity, in combination with rifampicin (RIF) against Mycobacterium tuberculosis has not been fully elucidated.

Aims: The aim of this study was to evaluate the in vitro activity of RIF/LZD combination against M. tuberculosis clinical isolates.

Materials and methods: The activity of the RIF/LZD combination was firstly determined in M. tuberculosis H₃₇Rv, 14 susceptible, 9 isoniazid nonresistant and 14 multi-drug resistant (MDR) M. tuberculosis clinical isolates by modified checkerboard assay, Resazurin Drugs Combination Microtiter Assay (REDCA). After, the Time Kill Curve Assay, at 0.5 × MIC of drugs, in combination and alone, was performed in M. tuberculosis H₃₇Rv and 8 (20.5%) of those clinical isolates, which the RIF/LZD combination showed to have synergistic effect by the checkerboard assay.

Results and conclusion: By Time Kill Curve Assay, we could observe in M. tuberculosis H₃₇Rv and susceptible isolates, that LZD alone, at sub inhibitory concentration, has poor effect on the bacillus death. In some cases, the bacillus growth stayed constant while in others showed regrowth at the eighth day of drug exposure. RIF alone exhibits potent concentration-dependent bactericidal activity, and was strongly dependent by the drug exposure time. The RIF/LZD combination accomplished a bacteriostatic effect in the reference strain and susceptible isolates. For the RIF resistant isolates, the RIF/LZD combination did not enhance the effect in killing bacillus. In this sense, additional, in vitro and in vivo studies are needed to evaluate the effect of RIF/LZD combination in order to better understand the adjunctive action of LZD in the treatment of TB and prevent the emergence of mutants with resistance to the available anti-TB drugs.

Keywords: Drug resistance; Linezolid and rifampicin combination; Treatment; Tuberculosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / pharmacology*
Drug Resistance, Multiple, Bacterial
Drug Synergism
Drug Therapy, Combination
Genotype
Linezolid / pharmacology*
Microbial Sensitivity Tests
Microbial Viability / drug effects
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / genetics
Mycobacterium tuberculosis / growth & development
Rifampin / pharmacology*
Time Factors

Substances

Antitubercular Agents
Linezolid
Rifampin