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Antibacterial Peptides
Article

Excretion of the Polymyxin Derivative NAB739 in Murine Urine

1
Northern Antibiotics Ltd., FI-02150 Espoo, Finland
2
Department of Bacteriology and Immunology, Helsinki University Medical School, FI-00014 Helsinki, Finland
3
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. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040143

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. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040143

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. https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040143

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