Martti Vaara1,2,3, Timo Vaara1, Carina Vingsbo Lundberg4. 1. Northern Antibiotics Ltd, Technopolis, Tekniikantie 14, FI-02150 Espoo, Finland. 2. Division of Clinical Microbiology, Helsinki University Hospital, FI-00029 Helsinki, Finland. 3. Department of Bacteriology and Immunology, Helsinki University Medical School, FI-00014 Helsinki, Finland. 4. Statens Serum Institut, Copenhagen, Denmark.
Abstract
Objectives: Extremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree. Here we have compared the efficacy of these NAB compounds and polymyxin B in the therapy of murine pyelonephritis caused by E. coli. Methods: The challenge organism was a uropathogenic E. coli clinical isolate. Mice were inoculated via urethral catheterization with 5 × 108 cfu. All treatment groups consisted of 12 animals. On day 1 and day 2 post-infection, the mice were treated subcutaneously with NAB739, NAB815, polymyxin B or vehicle twice a day and on day 3 post-infection the animals were sacrificed. cfu in the kidney and bladder tissues and in the urine were determined. Results: NAB739 reduced the bacterial burden in the kidney, urine and bladder at doses approximately 10-fold lower than those of polymyxin B. In the kidneys, the half-maximal effective dose (ED50) was 9-fold lower for NAB739 than for polymyxin B (0.24 mg/kg versus 2.1 mg/kg, respectively). NAB815 was as effective as NAB739. Conclusions: NAB739 and NAB815 were unequivocally more effective than polymyxin B in the murine pyelonephritis model.
Objectives: Extremely multiresistant strains of Enterobacteriaceae, such as those of Escherichia coli and Klebsiella pneumoniae, are emerging and spreading at a worrisome speed. Polymyxins (polymyxin B, colistin) are used as last-line therapy against such strains, in spite of their notable nephrotoxicity that may even require discontinuation of the therapy. We have previously developed polymyxin derivatives NAB739 and NAB815 that are better tolerated in cynomolgus monkeys than polymyxin B and are, in contrast to polymyxin B, excreted in the cynomolgus urine to a very significant degree. Here we have compared the efficacy of these NAB compounds and polymyxin B in the therapy of murinepyelonephritis caused by E. coli. Methods: The challenge organism was a uropathogenic E. coli clinical isolate. Mice were inoculated via urethral catheterization with 5 × 108 cfu. All treatment groups consisted of 12 animals. On day 1 and day 2 post-infection, the mice were treated subcutaneously with NAB739, NAB815, polymyxin B or vehicle twice a day and on day 3 post-infection the animals were sacrificed. cfu in the kidney and bladder tissues and in the urine were determined. Results: NAB739 reduced the bacterial burden in the kidney, urine and bladder at doses approximately 10-fold lower than those of polymyxin B. In the kidneys, the half-maximal effective dose (ED50) was 9-fold lower for NAB739 than for polymyxin B (0.24 mg/kg versus 2.1 mg/kg, respectively). NAB815 was as effective as NAB739. Conclusions: NAB739 and NAB815 were unequivocally more effective than polymyxin B in the murinepyelonephritis model.
Authors: Elijah J Weber; Kevin A Lidberg; Lu Wang; Theo K Bammler; James W MacDonald; Mavis J Li; Michelle Redhair; William M Atkins; Cecilia Tran; Kelly M Hines; Josi Herron; Libin Xu; Maria Beatriz Monteiro; Susanne Ramm; Vishal Vaidya; Martti Vaara; Timo Vaara; Jonathan Himmelfarb; Edward J Kelly Journal: JCI Insight Date: 2018-12-20
Authors: Martti Vaara; Timo Vaara; Janis Kuka; Eduards Sevostjanovs; Solveiga Grinberga; Maija Dambrova; Edgars Liepinsh Journal: Antibiotics (Basel) Date: 2020-03-27