Abstract
The in vitro activity of HSR-903, an oral quinolone, against 196 recent clinical isolates of respiratory pathogens was evaluated. HSR-903 was 2 to 32 times more active than ofloxacin, ciprofloxacin, and sparfloxacin against Staphylococcus aureus, including methicillin-resistant strains, and Streptococcus pneumoniae and was at least as active as the other quinolones against gram-negative pathogens.
HSR-903 is a new, oral quinolone with the chemical structure (S)-(−)-5-amino-7-(7-amino-5-azaspiro[2.4]hept-5-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methyl-1-4-oxoquinoline-3-carboxylic acid methanesulfonate. It was first synthesized by Hokuriku Pharmaceutical Co. Ltd., Fukui, Japan (2, 5), and has been shown to possess a potent, broad-spectrum in vitro activity (3) and a half-life of 17 to 18 h (4), which is long compared with those of closely related quinolones. The aim of the present study was to assess the in vitro activity of HSR-903, in comparison with those of other oral quinolones, against isolates from patients with respiratory tract infections.
The antimicrobials studied were HSR-903 (provided by Hokuriku Pharmaceutical Co. Ltd.), ofloxacin (Dai-ichi Pharmaceutical Co. Ltd., Tokyo, Japan), ciprofloxacin (Bayer Yakuhin Co. Ltd., Osaka, Japan), and sparfloxacin (Dainippon Pharmaceutical Co. Ltd., Osaka, Japan). A total of 196 clinical isolates from in- and outpatients in the Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging and Cancer, Tohoku University, were identified between January and December 1997 by using the API STAPH or the API STREP system (bioMérieux sa, Marcy l’Etoile, France) for Staphylococcus species and Streptococcus species, respectively; the Enterotube II system and the Oxyfermtube II system (Becton Dickinson and Company, Cockeysville, Md.) for members of the family Enterobacteriaceae and Pseudomonas species, respectively; and the ID TEST HN-20 Rapid system (Nissui Pharmaceutical Co. Ltd., Tokyo, Japan) for Haemophilus species and Moraxella species. Twenty strains each of methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa and 16 strains of Moraxella catarrhalis thus identified were used in this study.
MICs were determined by the broth microdilution method in 0.1 ml of cation-adjusted Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) according to the approved standard of the Japan Society of Chemotherapy (1). Strepto-Haemo supplement (8%; Eiken Co. Ltd., Tokyo, Japan), containing 5% horse hemolysate, 15 μg of NAD per ml, and 5 mg of yeast extract per ml at final concentration, was added to the Mueller-Hinton broth for the culture of S. pneumoniae, H. influenzae, and M. catarrhalis. Microdilution plates received an inoculum of about 5 × 105 CFU/ml delivered by means of an automatic pin inoculator (MDS 1,300; Dainippon Seiki Co. Ltd., Kyoto, Japan). The MIC was defined as the lowest antimicrobial concentration which inhibited visible growth after incubation for 20 h at 37°C. S. pneumoniae, H. influenzae, and M. catarrhalis were cultured in an incubator with 7% CO2 for 20 h at 32, 35, and 37°C, respectively.
Table 1 summarizes the MICs of the four antimicrobials for the strains tested. HSR-903 was 2 to 32 times more active than the other agents against gram-positive bacteria, including MSSA, MRSA, and S. pneumoniae. The antibacterial activity of HSR-903 was equal to or more potent than those of the other agents against E. coli, K. pneumoniae, E. cloacae, S. marcescens, and P. aeruginosa. Against H. influenzae and M. catarrhalis, HSR-903 had a potency similar to those of the other quinolones. Against S. pneumoniae, the most frequent pathogen in respiratory tract infections, the MIC at which 50% of the isolates are inhibited (MIC50) and MIC90 of HSR-903 were 0.06 and 0.12 μg/ml, respectively. HSR-903 showed a good maximum concentration in serum (0.86 μg/ml) and a long elimination half-life (18 h) in a pharmacokinetic study with human volunteers given a single 200-mg dose (4). In murine lungs, the area under the curve and maximum concentration in serum of HSR-903 were much higher than those in plasma (6). The in vitro potency of HSR-903, supported by its pharmacokinetics, suggests that HSR-903 should be useful in the treatment of respiratory tract infections.
TABLE 1.
Susceptibilities of recent clinical isolates of respiratory pathogens to the antimicrobials used in this study
| Microorganism | No. of isolates tested | Antimicrobial agent | MIC (μg/ml)
|
||
|---|---|---|---|---|---|
| Range | 50%a | 90%b | |||
| MSSA | 20 | HSR-903 | ≦0.03–0.06 | 0.06 | 0.06 |
| Ofloxacin | 0.12–0.5 | 0.25 | 0.5 | ||
| Ciprofloxacin | 0.12–1 | 0.25 | 0.5 | ||
| Sparfloxacin | 0.06–0.12 | 0.06 | 0.12 | ||
| MRSA | 20 | HSR-903 | ≦0.03–2 | 0.5 | 2 |
| Ofloxacin | 0.5–32 | 16 | 32 | ||
| Ciprofloxacin | 2–>64 | 16 | >64 | ||
| Sparfloxacin | 0.06–16 | 8 | 16 | ||
| S. pneumoniae | 20 | HSR-903 | ≦0.03–0.12 | 0.06 | 0.12 |
| Ofloxacin | 0.12–2 | 1 | 2 | ||
| Ciprofloxacin | 0.25–2 | 1 | 2 | ||
| Sparfloxacin | 0.06–0.5 | 0.25 | 0.5 | ||
| H. influenzae | 20 | HSR-903 | ≦0.03–0.06 | ≦0.03 | 0.06 |
| Ofloxacin | ≦0.03–0.06 | ≦0.03 | ≦0.03 | ||
| Ciprofloxacin | ≦0.03 | ≦0.03 | ≦0.03 | ||
| Sparfloxacin | ≦0.03–0.12 | ≦0.03 | 0.12 | ||
| M. catarrhalis | 16 | HSR-903 | ≦0.03 | ≦0.03 | ≦0.03 |
| Ofloxacin | ≦0.03–0.12 | 0.06 | 0.06 | ||
| Ciprofloxacin | ≦0.03–0.06 | ≦0.03 | 0.06 | ||
| Sparfloxacin | ≦0.03 | ≦0.03 | ≦0.03 | ||
| E. coli | 20 | HSR-903 | ≦0.03 | ≦0.03 | ≦0.03 |
| Ofloxacin | ≦0.03–0.5 | ≦0.03 | 0.25 | ||
| Ciprofloxacin | ≦0.03–0.25 | ≦0.03 | 0.25 | ||
| Sparfloxacin | ≦0.03–0.12 | ≦0.03 | 0.06 | ||
| K. pneumoniae | 20 | HSR-903 | ≦0.03–0.12 | ≦0.03 | 0.12 |
| Ofloxacin | ≦0.03–0.5 | 0.06 | 0.5 | ||
| Ciprofloxacin | ≦0.03–0.25 | ≦0.03 | 0.25 | ||
| Sparfloxacin | ≦0.03–0.5 | ≦0.03 | 0.25 | ||
| E. cloacae | 20 | HSR-903 | ≦0.03–0.25 | ≦0.03 | 0.25 |
| Ofloxacin | 0.06–2 | 0.25 | 1 | ||
| Ciprofloxacin | ≦0.03–1 | 0.12 | 1 | ||
| Sparfloxacin | ≦0.03–1 | ≦0.03 | 1 | ||
| S. marcescens | 20 | HSR-903 | ≦0.03–1 | 0.12 | 1 |
| Ofloxacin | 0.12–4 | 0.25 | 2 | ||
| Ciprofloxacin | ≦0.03–2 | 0.12 | 1 | ||
| Sparfloxacin | 0.25–8 | 0.5 | 4 | ||
| P. aeruginosa | 20 | HSR-903 | ≦0.03–0.25 | 0.12 | 0.25 |
| Ofloxacin | 0.25–2 | 1 | 2 | ||
| Ciprofloxacin | ≦0.03–0.25 | 0.12 | 0.25 | ||
| Sparfloxacin | 0.06–2 | 0.5 | 1 | ||
MIC50.
MIC90.
Acknowledgments
This work was supported partially by a grant for the “Study of Drug-Resistant Bacteria” from the Ministry of Health and Welfare, Japan.
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