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Antimicrobial Agents and Chemotherapy, June 2007, p. 2278-2279, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01561-06

LETTER TO THE EDITOR

Activity of Garenoxacin against Macrolide-Susceptible and -Resistant Mycoplasma pneumoniae{triangledown}


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In the treatment of Mycoplasma pneumoniae infection, erythromycin and clarithromycin, 14-membered macrolides, and azithromycin, a 15-membered macrolide, are usually considered to be the first-choice drugs (4, 11). Macrolide antibiotics inhibit protein synthesis by binding to domain II and/or domain V of 23S rRNA (1, 13). We found that ca. 20% of M. pneumoniae strains isolated from patients in Japan from 2000 to 2003 were macrolide resistant (6, 9). Lucier et al. (5) and Okazaki et al. (7) found that an A-to-G transition or an A-to-C transversion at position 2063 (corresponding to position 2058 in Escherichia coli) or 2064 of the 23S rRNA gene results in a high level of resistance to macrolide antibiotics. Given this background, it was considered that an alternative to macrolides in the treatment of pneumonia caused by M. pneumoniae is needed.

Garenoxacin, a des-F(6)-quinolone that exhibits excellent activity against respiratory pathogens such as Streptococcus pneumoniae and Chlamydophila pneumoniae, is under development for both oral and parenteral administration (10). In the present study, we examined the in vitro activity of garenoxacin against M. pneumoniae isolates, including macrolide-resistant strains, and compared it with those of other antibiotics.

The following agents were employed for MIC determinations: garenoxacin (Toyama Chemical Co., Ltd., Tokyo, Japan), gatifloxacin (Kyorin Pharmaceutical Co., Ltd., Tokyo, Japan), levofloxacin and clarithromycin (LKT Laboratories, Inc., Saint Paul, MN), and minocycline (Lederle-Japan Ltd., Tokyo, Japan). The purity of each of these agents was above 99.8%. The following isolates of M. pneumoniae were tested: three macrolide-susceptible reference strains, FH, Mac, and M129, and four macrolide-resistant clinical isolates, 1 and 6 (isolates carrying the A-to-G mutation at position 2063 in the 23S rRNA gene for which the MIC of clarithromycin is 32 µg/ml) and 2 and 4 (isolates carrying the A-to-G mutation at position 2064 in the 23S rRNA gene for which the MIC of clarithromycin is 8 µg/ml). The PCR amplification and sequencing of domain II of the 23S rRNA genes were performed by a method reported previously (6).

A broth microdilution method was used to determine the MICs. Serial twofold dilutions of antibacterial agents prepared in PPLO broth (Difco Inc., Detroit, MI) containing 104 to 105 CFU of M. pneumoniae/ml were put into 96-well microplates. The microplates were sealed with adhesive sheets and incubated at 37°C for 4 to 8 days. The MIC was defined as the lowest concentration of a drug at which the metabolism of the organism was inhibited, as evidenced by a lack of color change in the medium at the time when the drug-free control first showed a color change.

The MICs of garenoxacin for the M. pneumoniae isolates, including the macrolide-resistant isolates, were 0.016 to 0.031 µg/ml, two- to fourfold lower than those of gatifloxacin and 8- to 32-fold lower than those of levofloxacin and minocycline (Table 1). The results for macrolide-susceptible strains such as M. pneumoniae FH, a reference strain, accorded with those given in previous reports (2, 8, 12).


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  		TABLE 1. Activities of various antibiotics against M. pneumoniae strains

 
The newer fluoroquinolones such as gatifloxacin and moxifloxacin exhibit potent in vitro activity against a broad spectrum of organisms, including M. pneumoniae (3). Garenoxacin showed more-potent in vitro activity against M. pneumoniae than gatifloxacin and has attracted interest as a potential therapy for community-acquired pneumonia. These data indicate that garenoxacin may be a viable alternative to macrolides, such as clarithromycin, in the treatment of pneumonia caused by M. pneumoniae, including macrolide-resistant strains.


   FOOTNOTES
 
{triangledown} Published ahead of print on 26 March 2007. Back


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  1. Douthwaite, S., L. H. Hansen, and P. Mauvais. 2000. Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA. Mol. Microbiol. 36:183-193.[CrossRef][Medline]
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  3. Kenny, G. E., and F. D. Cartwright. 2001. Susceptibilities of Mycoplasma hominis, M. pneumoniae, and Ureaplasma urealyticum to GAR-936, dalfopristin, dirithromycin, evernimicin, gatifloxacin, linezolid, moxifloxacin, quinupristin-dalfopristin, and telithromycin compared to their susceptibilities to reference macrolides, tetracyclines, and quinolones. Antimicrob. Agents Chemother. 45:2604-2608.[Abstract/Free Full Text]
  4. Langtry, H. D., and J. A. Balfour. 1998. Azithromycin. A review of its use in pediatric infectious diseases. Drugs 56:273-297.[CrossRef][Medline]
  5. Lucier, T. S., K. Heitzman, S. K. Liu, and P. C. Hu. 1995. Transition mutations in the 23S rRNA of erythromycin-resistant isolates of Mycoplasma pneumoniae. Antimicrob. Agents Chemother. 39:2770-2773.[Abstract]
  6. Matsuoka, M., M. Narita, N. Okazaki, H. Ohya, T. Yamazaki, K. Ouchi, I. Suzuki, T. Andoh, T. Kenri, Y. Sasaki, A. Horino, M. Shintani, Y. Arakawa, and T. Sasaki. 2004. Characterization and molecular analysis of macrolide-resistant Mycoplasma pneumoniae clinical isolates obtained in Japan. Antimicrob. Agents Chemother. 48:4624-4630.[Abstract/Free Full Text]
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  9. Suzuki, S., T. Yamazaki, M. Narita, N. Okazaki, I. Suzuki, T. Andoh, M. Matsuoka, T. Kenri, Y. Arakawa, and T. Sasaki. 2006. Clinical evaluation of macrolide-resistant Mycoplasma pneumoniae. Antimicrob. Agents Chemother. 50:709-712.[Abstract/Free Full Text]
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Tsutomu Yamazaki
Department of Pediatrics
Saitama Medical School
Morohongo 38
Moroyama Iruma
Saitama 350-0495, Japan

Tsuguo Sasaki
Department of Bacterial Pathogenesis and Infection Control
National Institute of Infectious Diseases
Gakuen, 4-7-1
Musashimurayama-shi
Tokyo 162-8640, Japan

Masahiro Takahata*
Research Laboratories
Toyama Chemical Co., Ltd.
4-1, Shimookui 2-chome
Toyama 930-8508, Japan

* Phone: 81-764-31-8268
Fax: 81-764-31-8208
E-mail: masahiro_takahata{at}toyama-chemical.co.jp

Antimicrobial Agents and Chemotherapy, June 2007, p. 2278-2279, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01561-06




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