Activities of newer fluoroquinolones against ciprofloxacin-resistant Streptococcus pneumoniae.

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 < or =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 < or =31.7 and C(max)/MIC ratios of < or =3.1. It is evident that the newer fluoroquinolones tested possess improved activity against S. pneumoniae, including strains for which ciprofloxacin MICs were elevated.

Activity of oritavancin (LY333328), an investigational glycopeptide, compared to that of vancomycin against multidrug-resistant Streptococcus pneumoniae in an in vitro pharmacodynamic model.

In the past 2 decades, multidrug-resistant Streptococcus pneumoniae has been encountered with increasing frequency around the world. This has led to the need for newer agents in the treatment of S. pneumoniae infections. Oritavancin (LY333328) is a new glycopeptide antibiotic with activity against gram-positive organisms; however, there is limited information on the pharmacodynamics of oritavancin with respect to the treatment of S. pneumoniae. We utilized an in vitro pharmacodynamic model to compare the activity of oritavancin to that of vancomycin against two penicillin-, macrolide-, and ciprofloxacin-resistant S. pneumoniae isolates (R919 and R921) over a 48-h period. Both oritavancin and vancomycin achieved 99.9% (3-log) kill, with oritavancin achieving the limit of detection (10(2) CFU/ml) within 1 h and vancomycin achieving this limit at 24 h for both isolates. Detection of resistance was not observed for oritavancin or vancomycin during the 48-h experiments. The key pharmacodynamic parameter for oritavancin has not been well defined. In our experiment, the ratios of the area under the curve from 0 to 24 h to the MIC of oritavancin, oritavancin plus albumin, and vancomycin for both isolates were greater than 944.5, and the ratios of the maximum concentration of drug in serum to the MIC ranged from 73.7 to 7188.5. T>MIC was 100% for oritavancin and vancomycin for both isolates. Oritavancin is a unique and potent antimicrobial that warrants further investigation against multidrug-resistant S. pneumoniae.

Comparison of a rabbit model of bacterial endocarditis and an in vitro infection model with simulated endocardial vegetations.

Animal models are commonly used to determine the efficacy of various antimicrobial agents for treatment of bacterial endocarditis. Previously we have utilized an in vitro infection model, which incorporates simulated endocardial vegetations (SEVs) to evaluate the pharmacodynamics of various antibiotics. In the present study, we compared four experimental rabbit endocarditis protocols to an in vitro infection model in an effort to determine if these models are comparable. We have evaluated the activity of clinafloxacin, trovafloxacin, sparfloxacin, and ciprofloxacin in rabbit models against Staphylococcus aureus and Enterococcus spp. In vitro models were performed simulating the antibiotic pharmacokinetics obtained in the in vivo studies. Models were dosed the same as rabbit models, and SEVs were evaluated at the same time the rabbit vegetations were examined. Clinafloxacin and trovafloxacin were evaluated against methicillin-susceptible (MSSA1199) and -resistant (MRSA494) strains of S. aureus. Ciprofloxacin was studied against MSSA1199 and MSSA487. Sparfloxacin and clinafloxacin were evaluated against Enterococcus faecium SF2149 and Enterococcus faecalis WH245, respectively. We found that reductions in SEV bacterial density obtained in the in vitro model were similar to those obtained in rabbit vegetations, indicating that the SEV model may be a valuable tool for assessing antibiotic potential in the treatment of bacterial endocarditis.