n-6 Polyunsaturated Fatty Acids Enhance the Activities of Ceftazidime and Amikacin in Experimental Sepsis Caused by Multidrug-Resistant Pseudomonas aeruginosa

Abstract

Recent in vitro and ex vivo studies disclosed an enhancement of the activity of antimicrobials on multidrugresistant Pseudomonas aeruginosa by n-6 polyunsaturated fatty acids (PUFAS); therefore their effect was evaluated in experimental sepsis in 60 rabbits. Solutions of gamma-linolenic acid (GLA) and arachidonic acid (AA) were administered intravenously with ceftazidime and amikacin in rabbits with sepsis caused by one multidrug-resistant isolate. Therapy was started after bacterial challenge in five groups comprising 12 animals in each group: A, normal saline; B, antimicrobials; C, 99% ethanol and antimicrobials; D, GLA and antimicrobials; and E, AA and antimicrobials. Blood was sampled for the estimation of levels of endotoxins in serum (lipopolysaccharide), leukocytes, tumor necrosis factor alpha (TNF-␣) and antimicrobials. Animals were sacrificed 210 min after bacterial challenge for tissue cultures. All animals had considerable endotoxemia and evolved leukopenia. The number of viable cells in blood, lung, and mesenteric lymph nodes was significantly reduced in groups D and E compared to that in other groups. Levels of antimicrobials in serum were inadequate to achieve bacterial killing due to the level of resistance. n-6 PUFAs did not influence TNF-␣. It is concluded that intravenous coadministration of n-6 PUFAs and antimicrobials enhanced antimicrobial bacterial killing in experimental sepsis caused by multidrug-resistant P. aeruginosa.Pseudomonas aeruginosa is a major nosocomial pathogen characterized by multidrug resistance. It has been previously shown by our study group that n-6 polyunsaturated fatty acids (PUFAs) like gamma-linolenic acid (C 18:3 ; GLA) and arachidonic acid (C 20:4 ; AA) may enhance the in vitro activity of ceftazidime and amikacin and render multidrug-resistant isolates susceptible to the combination of these antimicrobials (9). In proximity to in vitro findings, it was documented that serum sampled after the intravenous administration of one AA solution may ex vivo enhance the effect of ceftazidime and amikacin on multidrug-resistant P. aeruginosa (10).Based on these previous findings, a solution of GLA and AA was administered intravenously with ceftazidime and amikacin for the therapy of an experimental model of sepsis caused by multidrug-resistant P. aeruginosa. The study attempted to simulate conditions of nosocomial sepsis treated by a combination of antimicrobials often inactive versus the causative pathogen (i.e., to a state where enhancement of the effect of antimicrobials is mandatory). MATERIALS AND METHODS Animals.A total of 60 New Zealand White male rabbits of a mean (Ϯ standard deviation [SD]) weight of 3.39 Ϯ 0.33 kg were studied. The study received a permit from the Veterinary Directorate of the Perfecture of Athens according to the Greek legislation in conformance with the 160/91 Directive Council of the European Union. Animals were housed in single metal cages and had access to tap water and standard balanced rabbit chow ad libitum. Room temperature ranged between...

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