Despite recent caveats about the rapid development of resistance to fluoroquinolones in the treatment of urinary tract infections (UTI), the good tolerability, bioavailability and the broad antibiotic spectrum of fluoroquinolons explain their increased use. We investigated the changes of bacterial spectra and cross resistance profiles in ambulatory and hospitalized UTI patients. A total of 430 positive urine cultures and resistograms were classified according to patient status as either ambulatory or hospitalized and retrospectively analyzed. Cross-resistance profiles of the most effective antibiotics (cotrimoxazol, levofloxacin, amoxicillin/clavulanic acid) were made before an analysis of cost-effectiveness was performed. Whereas Escherichia coli remains the predominant cause of UTI in ambulatory patients, Enterococcus faecalis is the most frequently detected bacterium in the urine cultures of hospitalized patients. This is one reason for the unacceptably high rate of primary resistance of UTI bacteria against cephalosporins. Primary resistance to cotrimoxazol, amoxicillin/cavulanic acid and levofloxacin are impressive and tend to favor the use of levofloxacin. However, high cross-resistance rates reduce the usability of one antibiotic in case of the lack of effectiveness of the other. The broad use of potent antibiotics in hospitals has led to a higher primary resistance and cross-resistance of UTI bacteria in hospitalized patients than in ambulatory patients. The primary resistance of UTI causing bacteria is generally high and worrying. The new fluoroquinolone levofloxacin exhibits surprisingly high primary resistance rates and shares high cross-resistance with other antibiotics that are as effective but much cheaper. Thus, we consider that it should not be a first line treatment option for ambulatory UTI patients in the absence of any resistogram, in order to ensure cost-effectiveness and a slow down in the rapid development of resistance.