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

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. The serum samples were spiked according to the median and minimum plasma peak concentrations measured in a phase 1 clinical study, in which seven healthy subjects received 3-times (q12) 1h-IV-infusions of 4, 2 and 2 million international units (MIU) colistin-methanesulfonate (CMS) co-administered with 200, 100 and 100 mg AZT, respectively. This trial was performed to assess the pharmacokinetics and safety of CMS/AZT-combination therapy. Minimal bactericidal concentrations of CS in native, but not heat-inactivated serum, were strongly reduced compared to 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 dosage was already bactericidal in native and heat-inactivated serum. Median, but not minimum, CS concentrations after 2 MIU CMS dosage were sufficient to kill the serum-resistant, colistin-resistant E.coli strain in native serum. In heat-inactivated serum, even the median CS concentration after 2 MIU CMS dosage 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, the combination with AZT potentiates the bactericidal effect of colistin against colistin-resistant E.coli strains. 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 the dosing should be further optimized.