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Antimicrobial Agents and Chemotherapy, June 2001, p. 1654-1659, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1654-1659.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Activities of Newer Fluoroquinolones against Ciprofloxacin-Resistant Streptococcus pneumoniae

Elizabeth A. Coyle,1,2 Glenn W. Kaatz,2,3,4 and Michael J. Rybak1,2,3,*

The Anti-Infective Research Laboratory and Department of Pharmacy Services, Detroit Receiving Hospital and University Health Center,1 College of Pharmacy and Allied Health Professions,2 and Division of Infectious Diseases, Department of Internal Medicine, School of Medicine,3 Wayne State University, and Department of Veterans Affairs Medical Center,4 Detroit, Michigan

Received 7 August 2000/Returned for modification 29 December 2000/Accepted 7 March 2001

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 (AUC0-24)/MIC and maximum concentration of drug in serum (Cmax)/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 AUC0-24/MIC ratios of <= 31.7 and Cmax/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.

* Corresponding author. Mailing address: The Anti-Infective Research Laboratory, Department of Pharmacy Services, Detroit Receiving Hospital and University Health Center, 4201 St. Antoine, Detroit, MI 48201. Phone: (313) 745-4554. Fax: (313) 993-2522. E-mail: m.rybak{at}wayne.edu.

Antimicrobial Agents and Chemotherapy, June 2001, p. 1654-1659, Vol. 45, No. 6
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.6.1654-1659.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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