title: Combination of amikacin and doxycycline against multidrug-resistant and extensively drug-resistant tuberculosis.
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.
authors.affiliation: National Mycobacterium Reference Laboratory, Public Health England, 2 Newark Street, London E1 2AT, UK; Centre for Immunology and Infectious Disease, Clinical TB and HIV Group, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK; Department of Infectious Diseases, Imperial College, The Commonwealth Building, The Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Ximena
authors.initials: X
authors.lastname: Gonzalo
authors.affiliation: Centre for Immunology and Infectious Disease, Clinical TB and HIV Group, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK; Department of Infectious Diseases, Imperial College, The Commonwealth Building, The Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Casali
authors.affiliation: Centre for Immunology and Infectious Disease, Clinical TB and HIV Group, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK; Department of Infectious Diseases, Imperial College, The Commonwealth Building, The Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Broda
authors.affiliation: Centre for Immunology and Infectious Disease, Clinical TB and HIV Group, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Pardieu
authors.affiliation: National Mycobacterium Reference Laboratory, Public Health England, 2 Newark Street, London E1 2AT, UK; Centre for Immunology and Infectious Disease, Clinical TB and HIV Group, Queen Mary University of London, 2 Newark Street, London E1 2AT, UK; Department of Infectious Diseases, Imperial College, The Commonwealth Building, The Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Electronic address: f.drobniewski@imperial.ac.uk.
authors.forename: Francis
authors.initials: F
authors.lastname: Drobniewski
mesh_terms: D000583:Amikacin / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000302:isolation & purification; D010865:Pilot Projects; D018088:Tuberculosis, Multidrug-Resistant / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D000583:Amikacin; D004318:Doxycycline
keywords: Amikacin; Doxycycline; Drug synergism; Microbial sensitivity tests; Multidrug-resistant; Tuberculosis