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Antimicrobial Agents and Chemotherapy, June 2002, p. 1651-1657, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1651-1657.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of Novel Nonfluorinated Quinolones PGE 9262932 and PGE 9509924 against Clinical Isolates of Staphylococcus aureus and Streptococcus pneumoniae with Defined Mutations in DNA Gyrase and Topoisomerase IV

Mark E. Jones,^1* Ian A. Critchley,² James A. Karlowsky,² Renée S. Blosser-Middleton,² Franz-Josef Schmitz,³ Clyde Thornsberry,² and Daniel F. Sahm²

Focus Technologies, Hilversum, The Netherlands,¹ Focus Technologies, Herndon, Virginia,² Institute for Medical Microbiology and Virology, Heinrich-Heine University Düsseldorf Hospital, Düsseldorf, Germany³

Received 15 November 2001/ Returned for modification 29 January 2002/ Accepted 22 February 2002

Two 8-methoxy nonfluorinated quinolones (NFQs), PGE 9262932 and PGE 9509924, were tested against contemporary clinical isolates of Staphylococcus aureus (n = 122) and Streptococcus pneumoniae (n = 69) with genetically defined quinolone resistance-determining regions (QRDRs). For S. aureus isolates with wild-type (WT) sequences at the QRDRs, the NFQs demonstrated activities 4- to 32-fold more potent (MICs at which 90% of isolates are inhibited [MIC₉₀s], 0.03 µg/ml) than those of moxifloxacin (MIC₉₀, 0.12 µg/ml), gatifloxacin (MIC₉₀, 0.25 µg/ml), levofloxacin (MIC₉₀, 0.25 µg/ml), and ciprofloxacin (MIC₉₀, 1 µg/ml). Against S. pneumoniae isolates with WT sequences at gyrA and parC, the NFQs PGE 9262932 (MIC₉₀, 0.03 µg/ml) and PGE 9509924 (MIC₉₀, 0.12 µg/ml) were 8- to 64-fold and 2- to 16-fold more potent, respectively, than moxifloxacin (MIC₉₀, 0.25 µg/ml), gatifloxacin (MIC₉₀, 0.5 µg/ml), levofloxacin (MIC₉₀, 2 µg/ml), and ciprofloxacin (MIC₉₀, 2 µg/ml). The MICs of all agents were elevated for S. aureus isolates with alterations in GyrA (Glu88Lys or Ser84Leu) and GrlA (Ser80Phe) and S. pneumoniae isolates with alterations in GyrA (Ser81Phe or Ser81Tyr) and ParC (Ser79Phe or Lys137Asn). Fluoroquinolone MICs for S. aureus strains with double alterations in GyrA combined with double alterations in GrlA were 32 µg/ml, whereas the MICs of the NFQs for strains with these double alterations were 4 to 8 µg/ml. The PGE 9262932 and PGE 9509924 MICs for the S. pneumoniae isolates did not exceed 0.5 and 1 µg/ml, respectively, even for isolates with GyrA (Ser81Phe) and ParC (Ser79Phe) alterations, for which levofloxacin MICs were >16 µg/ml. No difference in the frequency of selection of mutations (<10^-8 at four times the MIC) in wild-type or first-step mutant isolates of S. aureus or S. pneumoniae was detected for the two NFQs. On the basis of their in vitro activities, these NFQ agents show potential for the treatment of infections caused by isolates resistant to currently available fluoroquinolones.

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* Corresponding author. Mailing address: Focus Technologies, Koninginnweg 11, Hilversum, 1217 KP, The Netherlands. Phone: 31 35 625 7290. Fax: 31 35 625 7287. E-mail: mjones{at}focusanswers.com.

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Antimicrobial Agents and Chemotherapy, June 2002, p. 1651-1657, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1651-1657.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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