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Antimicrobial Agents and Chemotherapy, November 2004, p. 4113-4119, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4113-4119.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Telithromycin, Erythromycin, Azithromycin, and Clarithromycin against Haemophilus influenzae

Klaudia Kosowska,¹ Kim Credito,¹ Glenn A. Pankuch,¹ Dianne Hoellman,¹ Gengrong Lin,¹ Catherine Clark,¹ Bonifacio Dewasse,¹ Pamela McGhee,¹ Michael R. Jacobs,² and Peter C. Appelbaum^1*

Hershey Medical Center, Hershey, Pennsylvania,¹ Case Western Reserve University, Cleveland, Ohio²

Received 14 April 2004/ Returned for modification 23 May 2004/ Accepted 1 June 2004

The MIC at which 50% of strains are inhibited (MIC₅₀) and the MIC₉₀ of GW 773546, a novel macrolide, were 1.0 and 2.0 µg/ml, respectively, for 223 ß-lactamase-positive, ß-lactamase-negative, and ß-lactamase-negative ampicillin-resistant Haemophilus influenzae strains. The MIC₅₀s and MIC₉₀s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 µg/ml, respectively, while the MIC₅₀ and MIC₉₀ of azithromycin were 1.0 and 2.0 µg/ml, respectively. The MIC₅₀ and MIC₉₀ of erythromycin were 4.0 and 8.0 µg/ml, respectively; and those of clarithromycin were 4.0 and 16.0 µg/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 x 10^–9 to 2.2 x 10^–6 with GW 773546, 1.5 x 10^–9 to 6.0 x 10^–4 with GW 708408, and 7.1 x 10^–9 to 3.8 x 10^–4 with telithromycin, whereas the frequencies were 1.3 x 10^–9 to 6.0 x 10^–4 with erythromycin and azithromycin and 2.0 x 10^–9 to 2.0 x 10^–3 with clarithromycin. Alterations in the L22 protein (which were predominant) and the L4 protein were present in mutants selected by the single-step selection process. The postantibiotic effects of GW 773546, GW 708408, and telithromycin for seven H. influenzae strains were 6.6 h (range, 5.2 to 8.8 h), 4.7 h (range, 2.6 to 6.9 h), and 6.4 h (range, 3.8 to 9.7 h), respectively. The results of in vitro studies obtained with both novel macrolides were similar to those obtained with telithromycin and better than those obtained with older macrolides.

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* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, Hershey, PA 17033. Phone: (717) 531-5113. Fax: (717) 531-7953. E-mail: pappelbaum{at}psu.edu.

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Antimicrobial Agents and Chemotherapy, November 2004, p. 4113-4119, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4113-4119.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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