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Serum bactericidal activity of colistin and azidothymidine combinations against mcr-1-positive colistin-resistant Escherichia coli

Loose, Maria, Naber, Kurt G., Hu, Yanmin, Coates, Anthony, Wagenlehner, Florian M.E.
International journal of antimicrobial agents 2018 v.52 no.6 pp. 783-789
Escherichia coli, antibacterial properties, blood serum, colistin, humans, pharmacokinetics
To examine the serum bactericidal activity of colistin sulphate (CS) and azidothymidine (AZT) combinations, time–kill curves were performed in native and heat-inactivated human serum with five colistin-resistant and four colistin-susceptible Gram-negative strains. Serum samples were spiked according to median and minimum plasma peak concentrations measured in a phase 1 clinical study in which seven healthy subjects received three (q12h) 1-h intravenous infusions of 4, 2 and 2 MIU colistin methanesulfonate (CMS) co-administered with 200, 100 and 100 mg AZT, respectively. This trial was performed to assess pharmacokinetics and safety of CMS/AZT combination therapy. Minimum bactericidal concentrations of CS in native, but not heat-inactivated, serum were strongly reduced compared with Mueller–Hinton broth for all tested Enterobacteriaceae, except one colistin-resistant (serum-resistant) strain. For colistin-susceptible strains, the minimum CS concentration after 2 MIU CMS was already bactericidal in native and heat-inactivated serum. Median, but not minimum, CS concentrations after 2 MIU CMS were sufficient to kill the serum-resistant, colistin-resistant Escherichia coli strain in native serum. In heat-inactivated serum, even the median CS concentration after 2 MIU CMS was not bactericidal for all colistin-resistant strains. In general, combinations with AZT accelerated killing of colistin-resistant E. coli or showed bactericidal activity even if the substances alone were not bactericidal. Thus, combination with AZT potentiates the bactericidal effect of colistin against colistin-resistant E. coli. Although the dosage of 2 MIU CMS plus AZT may be sufficient to treat infections with colistin-susceptible strains, for infections caused by colistin-resistant E. coli, dosing should be further optimised.