Activities of Newer Fluoroquinolones against Ciprofloxacin-Resistant Streptococcus pneumoniae

doi:10.1128/AAC.45.6.1654-1659.2001

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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 concernsregarding the clinical impact of potential cross-resistance withnewer fluoroquinolones. To investigate this problem, we utilizedan in vitro pharmacodynamic model and compared the activitiesof gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, andtrovafloxacin to that of ciprofloxacin against two laboratory-derived,ciprofloxacin-resistant derivatives of S. pneumoniae (strainsR919 and R921). Ciprofloxacin resistance in these strains involvedthe 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 achieved99.9% killing of both R919 and R921 in $<=$ 28 h. With respect tolevofloxacin, significant regrowth of both mutants was observedat 48 h (P < 0.05). For gatifloxacin, grepafloxacin, moxifloxacin,and trovafloxacin, regrowth was minimal at 48 h, with each maintaining99.9% killing against both mutants. No killing of either R919or R921 was observed with exposure to ciprofloxacin. During modelexperiments, resistance to gatifloxacin, grepafloxacin, moxifloxacin,and trovafloxacin did not develop but the MICs of ciprofloxacinand levofloxacin increased 1 to 2 dilutions for both R919 andR921. Although specific area under the concentration-time curvefrom 0 to 24 h (AUC_0-24)/MIC and maximum concentration ofdrug in serum (C_max)/MIC ratios have not been defined for thefluoroquinolones with respect to gram-positive organisms, ourstudy revealed that significant regrowth and/or resistance wasassociated with AUC_0-24/MIC ratios of $<=$ 31.7 and C_max/MICratios of $<=$ 3.1. It is evident that the newer fluoroquinolonestested possess improved activity against S. pneumoniae, includingstrains for which ciprofloxacin MICs wereelevated.

^* Corresponding author. Mailing address: The Anti-Infective Research Laboratory, Department of Pharmacy Services, Detroit ReceivingHospital 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.

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