No abstract

The uptake of quinolone antibiotics by Escherichia coli was investigated by using fleroxacin , AM 833) as a prototype compound. The uptake of fleroxacin was reduced and its MIC was increased in the presence of magnesium. Quinolones induced lipopolysaccharide release, increased cell-surface hydrophobicity and outer membrane permeability to l-lactams, and sensitized cells to lysis by detergents. These effects were also antagonized by magnesium and were very similar to those seen with EDTA and gentamicin. MICs of quinolones in porin-deficient strains were increased relative to those of the parent strain, consistent with a porin pathway of entry. However, MICs were further increased in the presence of magnesium; the size of the additional increase showed a positive correlation with quinolone hydrophobicity in an OmpF-OmpCOmpA-strain. When quinolones were mixed with divalent cations in solution, changes in quinolone fluorescence suggestive of metal chelation were observed. The addition of fleroxacin to a cell suspension resulted in a rapid initial association of fluorescence with cells, foUlowed by a brief decrease and a final time-dependent linear increase in cell-associated fluorescence. We interpret these results as representing chelation of outer membrane-bound magnesium by fleroxacin and other quinolones, dissociation of the quinolone-magneum complex from the outer membrane, and diffusion of the quinolone through both porins and exposed lipid domains on the outer membrane. For a given quinolone, the contribution of the porin and nonporin pathways to total uptake is influenced by the hydrophobicity of the quinolone.Quinolones are broad-spectrum antibacterial agents whose primary mechanism of action is inhibition of DNA gyrase activity (2). Access to the target site is a major determinant of antibacterial activity, the outer membrane being the major permeability barrier in gram-negative bacteria. Quinolones are known to penetrate the outer membrane of Escherichia coli through the OmpF and OmpC porins; this has been demonstrated by both the use of defined porindeficient strains (8) and the isolation of quinolone-resistant mutants that lack porins (9, 10). However, the size of the quinolone MIC increase in porin-deficient mutants relative to the wild type is rarely more than fourfold. In similar porin-deficient mutants, the MIC increases of hydrophilic cephalosporins, which are restricted to the use of porins (18,25), may be as much as 64-fold (11). Hirai et al. (8) noted that the MIC of quinolones was decreased in lipopolysaccharidedeficient (rough) mutants as compared with the wild type, and the size of the decrease correlated with the hydrophobicity of the quinolone. These observations suggested that the passage of quinolones through the outer membrane was not limited to porins.Several classes of antibiotics, including the aminoglycosides and polymyxin B, are known to penetrate the outer membrane by pathways other than porins (6). These molecules displace divalent cations which bridge adjacent lipopolysaccharide ...

No abstract

A cohort of survivors of congenital diaphragmatic hernia (CDH), with matched controls, was studied to assess growth, respiratory function, and exercise performance. Nineteen of 24 survivors from an 11 year period (79%) were compared with 19 matched controls. Subjects had detailed auxology, performed spirometry and cycle ergometry, and completed questionnaires about respiratory symptoms and exercise. There were no significant diVerences between the groups for height, weight, sitting height, head circumference, or body mass index expressed as SD scores. The mean (95% confidence interval) percentage predicted forced vital capacity (FVC) was 84.7% (79.1 to 90.3) in index cases and 96.5% (91.4 to 101.6) in controls (p < 0.01). There was no significant diVerence in total lung capacity. Expiratory flow rates corrected for FVC were also similar between groups, suggesting normal airway function relative to lung size. Mean maximum oxygen consumption in ml/kg/min was 40.1 (36.8 to 43.4) and 42.2 (38.5 to 45.8) in index and control cases. These diVerences were not significant. Index cases achieved a similar minute ventilation to controls by more rapid and shallower breathing. Index cases had lower perception of their own fitness and lower enjoyment of exercise, although habitual activity levels were similar. Survivors of CDH repair have reduced functional lung volumes, but normal airway function compared with matched controls. They have no growth impairment nor significant impairment of exercise performance, although they have more negative perceptions of their own fitness. They should be encouraged and expected to participate fully in sport and exercise. (Arch Dis Child 1998;78:137-142)

No abstract