Excretion of the Polymyxin Derivative NAB739 in Murine Urine

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.

Antibiotic resistance breakers: current approaches and future directions

“…2012). These second generation derivatives were patented by Vaara, Vaara and Northern Antibiotic Ltd (Vaara and Vaara 2009) in 2009 and subsequently licensed to Spero Therapeutics, where NAB741 was given the code SPR741. Corbett et al .…”

Urinary Excretion of Iohexol as a Permeability Marker in a Mouse Model of Intestinal Inflammation: Time Course, Performance and Welfare Considerations

“…This method is, however, susceptible to different contaminants such as stools or food, which may affect the results to an unknown greater or lesser degree. Alternatives to MCs such as hydrophobic sand [ 50 , 51 , 52 ] are refined techniques that have not been yet extensively used in rodents, unlike MCs. Efforts should be made to promote the implementation of easy-to-use, noninvasive, less stressful and less variable refined devices or methods for the collection of urine samples in rodents during IP testing.…”