The incidence of ciprofloxacin resistance in Streptococcus pneumoniae is low but steadily increasing, which raises concerns regarding the clinical impact of potential cross-resistance with newer fluoroquinolones. To investigate this problem, we utilized an in vitro pharmacodynamic model and compared the activities of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin to that of ciprofloxacin against two laboratory-derived, ciprofloxacin-resistant derivatives of S. pneumoniae (strains R919 and R921). Ciprofloxacin resistance in these strains involved the activity of a multidrug efflux pump and possibly, for R919, a mutation resulting in an amino acid substitution in GyrA. Gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin achieved 99.9% killing of both R919 and R921 in <28 h. With respect to levofloxacin, significant regrowth of both mutants was observed at 48 h (P < 0.05). For gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin, regrowth was minimal at 48 h, with each maintaining 99.9% killing against both mutants. No killing of either R919 or R921 was observed with exposure to ciprofloxacin. During model experiments, resistance to gatifloxacin, grepafloxacin, moxifloxacin, and trovafloxacin did not develop but the MICs of ciprofloxacin and levofloxacin increased 1 to 2 dilutions for both R919 and R921. Although specific area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC and maximum concentration of drug in serum (C max )/MIC ratios have not been defined for the fluoroquinolones with respect to gram-positive organisms, our study revealed that significant regrowth and/or resistance was associated with AUC 0-24 /MIC ratios of <31.7 and C max /MIC ratios of <3.1. It is evident that the newer fluoroquinolones tested possess improved activity against S. pneumoniae, including strains for which ciprofloxacin MICs were elevated.Streptococcus pneumoniae is a significant cause of morbidity and mortality and is one of the primary pathogens implicated in community-acquired pneumonia (2,3,5,17,36). Newer fluoroquinolones, such as levofloxacin, trovafloxacin, and clinafloxacin, have been shown to possess greater activity than older agents of this class against gram-positive organisms, including S. pneumoniae (3,6,8,13,19,23,34). The newer fluoroquinolones thus are potential alternatives for therapy of infections caused by multidrug-resistant pneumococci. With the increasing use of these drugs, however, there is growing concern regarding the development of quinolone resistance among gram-positive bacteria (10, 21).Animal models, in vitro pharmacodynamic models, and limited human data have demonstrated that the primary pharmacodynamic parameters which most closely correlate with therapeutic efficacy of fluoroquinolones are area under the concentration-time curve from 0 to 24 h (AUC 0-24 )/MIC and maximum concentration of drug in serum (C max )/MIC ratios (1,16,28,37). However, there are limited data correlating pharmacodynamic parameters with the devel...