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Antibacterial Peptides

Excretion of the Polymyxin Derivative NAB739 in Murine Urine

Northern Antibiotics Ltd., FI-02150 Espoo, Finland
Department of Bacteriology and Immunology, Helsinki University Medical School, FI-00014 Helsinki, Finland
Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Aizkraukles Str 21, LV1006 Riga, Latvia
Author to whom correspondence should be addressed.
Received: 27 February 2020 / Revised: 19 March 2020 / Accepted: 25 March 2020 / Published: 27 March 2020
(This article belongs to the Section Mechanisms of Antibiotic Action)
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. View Full-Text
Keywords: NAB739; polymyxin B; mouse pyelonephritis; extremely multiresistant strains of Enterobacteriaceae NAB739; polymyxin B; mouse pyelonephritis; extremely multiresistant strains of Enterobacteriaceae
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MDPI and ACS Style

Vaara, M.; Vaara, T.; Kuka, J.; Sevostjanovs, E.; Grinberga, S.; Dambrova, M.; Liepinsh, E. Excretion of the Polymyxin Derivative NAB739 in Murine Urine. Antibiotics 2020, 9, 143.

AMA Style

Vaara M, Vaara T, Kuka J, Sevostjanovs E, Grinberga S, Dambrova M, Liepinsh E. Excretion of the Polymyxin Derivative NAB739 in Murine Urine. Antibiotics. 2020; 9(4):143.

Chicago/Turabian Style

Vaara, Martti, Timo Vaara, Janis Kuka, Eduards Sevostjanovs, Solveiga Grinberga, Maija Dambrova, and Edgars Liepinsh. 2020. "Excretion of the Polymyxin Derivative NAB739 in Murine Urine" Antibiotics 9, no. 4: 143.

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