CONICET | Buscador de Institutos y Recursos Humanos

Clofibric acid (CL) is a compound used to control hypertriglyceridemia and ethacrynic acid (ET) is administered to enhance diuresis. These compounds are weak acids structurally analogous to the widely used herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) as they have a chlorinated phenoxy moiety. Since these agents are mainly excreted unaltered or conjugated by the renal route, they could potentially coexist with Escherichia coli in the urinary tract of infected patients undergoing antibiotic treatment. The induction of the in vitro resistance of E. coli to a wide variety of hydrophilic antibiotics was determined by increasing the values of minimum inhibitory concentration and/or minimum bactericidal concentration (2 to 40 folds). These results were correlated with a drastically inhibited expression of the hydrophilic bacterial channel OmpF. In vivo assays were performed by an experimental model of ascending urinary tract infection in female BALB/c mice. The treatment with the hydrophilic antibiotic cephalexin 25mg/kg/day by the oral route diminished renal infection. The colony forming unit (CFU) mean values in kidneys were between 75% and 89% lower than those in animals without treatment (between 2 and 15 days post-challenge with E. coli). Simultaneous exposure to CL (at therapeutic dose, 28.6 mg/kg/day) did not modify the effect of the treatment. On the contrary, ET at 2.9 mg/kg/day or 2,4-D at 70 mg/kg/day inhibited the antibiotic therapeutic effect. Moreover, 2,4-D dramatically increased bacterial infection after 9 days of exposure. The results suggest that 2,4-D and ET induce resistance to antibiotic therapy in urinary tract infection, probably related to the decreased permeability through the bacterial OmpF channel. CL did not modify cephalexin treatment in vivo, suggesting that the CL-glucuronid excreted had no effect on the E. coli susceptibility. The fact that these compounds affect the pathogenicy of uropathogenic strains by lowering their susceptibility to antibiotics, highlight the impact of frequently underestimated or ignored collateral effects of xenobiotics.