Excretion of the polymyxin derivative NAB739 in murine urine

Martti Vaara (Coresponding Author), Timo Vaara, Janis Kuka, Eduards Sevostjanovs, Solveiga Grinberga, Maija Dambrova (Coresponding Author), Edgars Liepinsh

Research output: Contribution to journalArticlepeer-review

Abstract

Extremely multiresistant strains of Enterobacteriaceae are emerging and spreading at a worrisome pace. Polymyxins are used as the last-resort therapy against such strains, in spite of their nephrotoxicity. We have previously shown that novel polymyxin derivatives NAB739 and NAB815 are less nephrotoxic in cynomolgus monkeys than polymyxin B and are therapeutic in murine Escherichia coli pyelonephritis at doses only one-tenth of that needed for polymyxin B. Here we evaluated whether the increased efficacy is due to increased excretion of NAB739 in urine. Mice were treated with NAB739 and polymyxin B four times subcutaneously at doses of 0.25, 0.5, 1, 2, and 4 mg/kg. In plasma, a clear dose–response relationship was observed. The linearity of Cmax with the dose was 0.9987 for NAB739 and 0.975 for polymyxin B. After administration of NAB739 at a dose of 0.25 mg/kg, its plasma concentrations at all tested time points were above 0.5 µg/mL while after administration at a dose of 0.5 mg/kg its plasma concentrations exceeded 1 µg/mL. The Cmax of NAB739 in plasma was up to 1.5-times higher after single (first) administration and up to two-times higher after the last administration when compared to polymyxin B. Polymyxin B was not detected in urine samples even when administered at 4 mg/kg. In contrast, the concentration of NAB739 in urine after single administration at a dose of 0.25 mg/kg was above 1 µg/mL and after administration of 0.5 mg/kg its average urine concentration exceeded 2 µg/mL. At the NAB739 dose of 4 mg/kg, the urinary concentrations were higher than 35 µg/mL. These differences explain our previous finding that NAB739 is much more efficacious than polymyxin B in the therapy of murine E. coli pyelonephritis.

Original languageEnglish
Article number143
JournalAntibiotics
Volume9
Issue number4
DOIs
Publication statusPublished - Apr 2020
Externally publishedYes

Keywords

  • Extremely multiresistant strains of Enterobacteriaceae
  • Mouse pyelonephritis
  • NAB739
  • Polymyxin B

Field of Science

  • 3.1 Basic medicine
  • 1.6 Biological sciences

Publication Type

  • 1.1. Scientific article indexed in Web of Science and/or Scopus database

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