Novel Antimicrobial Combination Show Activity Against Gram-Negative Uropathogens

An intravenous (IV) combination of colistin-methanesulfonate and azidothymidine (AZT) shows promise as a treatment for gram-negative uropathogens, including colistin-resistant Escherichia coli, according to a study published in the International Journal of Antimicrobial Agents.

This phase 1 clinical study was designed to assess the pharmacokinetics and safety of IV administration of AZT and colistin-methanesulfonate both alone and in combination. Seven healthy study participants were each given 3 rounds (every 12 hours) of 1-hour IV infusions of 4, 2, and 2 million international units (MIU) of colistin-methanesulfonate co-administered with 200, 100, and 100 mg of AZT, respectively. In an ex vivo study, researchers performed time-kill curve determinations and urinary bactericidal titers on samples of artificial urine spiked with AZT and colistin sulfate, using the minimum and median peak concentrations in urine measured after the first and the third dose, with 4 mcr-1 positive colistin-resistant and 5 colistin-susceptible gram-negative strains.

The reciprocal urinary bactericidal titers of the different colistin concentrations found in the urine ranged from 0 to 2 and 1 to 128 for colistin-resistant and colistin-susceptible strains, respectively. Combination with AZT increased urinary bactericidal titers up to 2 dilution steps for both the Acinetobacter and Enterobacteriaceae strains tested but did not show activity against Pseudomonas strains. Even when the substances themselves were not bactericidal, the combination did not show bactericidal activity against colistin-resistant strains in time-kill curves.

The researchers concluded, “In this part II ex vivo study, combination of [urinary bactericidal titers] with AZT shows promising activity against gram-negative uropathogens, including colistin-resistant E coli. According to the urinary bactericidal activity, a dosage of 2 MIU CMS plus 100 mg AZT is sufficient for the treatment of [urinary tract infection] with colistin-susceptible strains. In contrast, for [urinary tract infection] caused by colistin-resistant E. coli, the combination of 2 MIU CMS with 100 mg AZT showed good indications that AZT potentiates the bactericidal effect of colistin. However, a higher dosage should be tested in well-designed clinical studies.”

Reference

Loose M, Naber KG, Hu Y, Coates A, Wagenlehner FME. Urinary bactericidal activity of colistin and azidothymidine combinations against mcr-1 positive colistin-resistant Escherichia coli [published online April 26, 2019]. Int J Antimicrob Agents. doi: 10.1016/j.ijantimicag.2019.04.011