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Increasingly resistant bacteria in sickle cell disease patients indicate need to evaluate extendedspectrum cephalosporin therapy., Few long-term multicenter investigations have evaluated the relationships between aggregate antimicrobial drug use in hospitals and bacterial resistance. We measured fluoroquinolone use from 1999 through 2003 in a network of US hospitals. The percentages of fluoroquinolone-resistant Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) were obtained from yearly antibiograms at each hospital. Univariate linear regression showed significant associations between a hospital's volume of fluoroquinolone use and percent resistance in most individual study years (1999–2001 for P. aeruginosa, 1999–2002 for S. aureus). When the method of generalized estimating equations was used, a population-averaged longitudinal model incorporating total fluoroquinolone use and the previous year's resistance (to account for autocorrelation) did not show a significant effect of fluoroquinolone use on percent resistance for most drug-organism combinations, except for the relationship between levofloxacin use and percent MRSA. The ecologic relationship between fluoroquinolone use and resistance is complex and requires further study.