Patients with diarrhea due to strains of enterohemorrhagic Escherichia coli (EHEC) (e. g. O157:H7) might be at a higher risk of developing hemolytic uremic syndrome when treated with antimicrobial agents. It has been suggested that this might be due to an increase of release or production of vero or shiga-like toxin from such organisms, possibly as a stress response to antimicrobial agents. The aim of this study was to detect such increases in extracellular toxin in vitro with a newly developed method that exposed EHEC to high sublethal concentrations followed by a recovery phase at progressively lower concentrations. Five strains of EHEC were exposed to continuously changing concentrations of ciprofloxacin, co-trimoxazole, cefixime and tetracycline. The amount of free shiga-like toxin I (SLT-I) released was compared to the amount released from inocula that were not exposed to antibiotics. There were significant differences between the five EHEC strains in the amount of toxin detected after exposure to antimicrobial agents (p less than 0.001). Equally important was the type of antibiotic (p less than 0.001), with ciprofloxacin inducing the largest increase ranging from 169 to 436%, followed by co-trimoxazole, cefixime and tetracycline. In addition, the increases in free toxin correlated with the concentration of the antibiotics (p less than 0.001). The association between antibiotic-induced increases in SLT-I produced by strains of EHEC and certain classes of antibiotics might influence the analysis of future epidemiological studies on risk factors for HUS.

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This study was undertaken to compare the susceptibility to inactivation of isepamicin with amikacin and gentamicin when. exposed to different beta-lactams, ,I-lactamase inhibitors, and heparin. The aminoglycosides (5; 10, 20, and 50 ,g/ml) were incubated in human serum with ampicillin, azlocillin, aztreonam, carbenicillin, ceftazidime, piperacillin, and ticarcillin (100 and 600 ,ug/ml) and with clavulanate, cilastatin, 1:1 imipenemcilastatin? oxacilin, and sulbactam (20 and 120 ,ug/ml) for 48 h at 37°C. Aminoglycoside concentrations were measured by fluorescence polarization immunoassay (FPI) after 0, 8, and 48 h of incubation and by radial difibsion bipassay after 48 h of incubation. Each of the three aminoglycosides was also added to whole blood tontaihing either hebarin (100 U/ml) or 0.5% EDTA as a control and assayed after 6 h by FPI. The degree of inactivation of isepamicin by the beta-lactams was significantly less than that by amikacin (P < 0.003) and gentamAicih,(P < O.0.X2) when determined by bioassay. Piperacillin, carbenicillin, and azlocillin produced the greatest amount of inactivation, and cilastatin and oxacillin produced the least. A similar pattern was observed when the degree of inactivation ywvs measured by FPI. A significant difference in the degree of inactivation was noted between isepanticin and gentamicin (P < 0.003 at 8 h and P < 0.006 at 48 h) but not between isepamicin and amikacin (P> Q.7 at 8h and P > 0.08 at 48 h). Aminoglycoside determinations by FPI were not influenced by the,pirestnce of heparin. In summary, isepamicin was found to be at least as stable as amikacin against inactivration by beta-lactam compounds and Il-lactamase inhibitors. Heparin (100 U/ml) did not influence aminoglycoside determinations by FPL Aminoglycoside antibiotics interact with beta-lactam compounds and heparinr (11,12,14). The mechanism for the interaction with beta-lactams is thought to consist of a nuc1 ophilic opening of the beta-lactam ring by an amino group, leading to formation of. an amide, with loss of biological activity of both (2). Heparin in contrast binds by ionic ijiteraction only, a process that is reversible by dilution (12). The concentrations of heparin that are used therapeutically are too low for this to occur in vivo, but sufficient concentrations can be reached in blood collection tubes (12).The inactivation of aminoglycosides by beta-lactam antibiotics is clinically relevant for patients with renal failure, in whom beta-lactams can accumulate to high concentrations and inactivate an aminoglycoside given concomitantly (4,11,16). Loss of the aminoglycoside due to in vitro inactivation can also occur when specimens containing both compounds are processed after delay (14). Tissue culture media frequently contain both types of antibiotics, and inactivation can limit the time for storage and exchange of media.Isepamicin is an aminoglycoside with increased stability against enzymatic degradation and low oto-and nephrotoxicity (9). Its sensitivity to inactivation by beta-lactam compounds ...

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