Combination of amikacin and doxycycline against multidrug-resistant and extensively drug-resistant tuberculosis

Ximena Gonzalo, Nicola Casali, Agnieszka Broda, Claire Pardieu, Francis Drobniewski*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

The objective of this study was to assess the activity of amikacin in combination with doxycycline against clinical strains of Mycobacterium tuberculosis in the search for new strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis. The study included 28 clinical M. tuberculosis strains, comprising 5 fully susceptible, 1 isoniazid-resistant, 17 MDR, 1 poly-resistant (streptomycin/isoniazid), 1 rifampicin-resistant and 3 XDR isolates, as well as the laboratory strain M. tuberculosis H37Rv. Minimum inhibitory concentrations (MICs) were determined using a modified chequerboard methodology in a BACTEC™ MGIT™ 960 System. Fractional inhibitory concentration indices (FICIs) were calculated, and synergy, indifference or antagonism was assessed. Whole-genome sequencing was performed to investigate the genetic basis of synergy, indifference or antagonism. The MIC50 and MIC90 values (MICs that inhibit 50% and 90% of the isolates, respectively) were, respectively, 0.5 mg/L and 1.0 mg/L for amikacin and 8 mg/L and 16 mg/L for doxycycline. The combination of amikacin and doxycycline showed a synergistic effect in 18 of the 29 strains tested and indifference in 11 strains. Antagonism was not observed. A streptomycin resistance mutation (K43R) was associated with indifference. In conclusion, the benefit of addition of doxycycline to an amikacin-containing regimen should be explored since in vitro results in this study indicate either synergy or indifference. Moreover, doxycycline also has immunomodulatory effects.

Original languageEnglish
Pages (from-to)406-412
Number of pages7
JournalInternational Journal of Antimicrobial Agents
Volume45
Issue number4
DOIs
Publication statusPublished - Apr 2015

Bibliographical note

Funding Information:
Funding: This study was supported by internal funding and by EU FP7 Programme Grant (PANNET).

Publisher Copyright:
© 2015 Published by Elsevier B.V.

Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.

Keywords

  • Amikacin
  • Doxycycline
  • Drug synergism
  • Microbial sensitivity tests
  • Multidrug-resistant
  • Tuberculosis

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