Central Research Laboratories, Kyorin Pharmaceutical Co., Ltd, 2399-1 Mitarai, Nogi, Shimotsuga, Tochigi 329-0114, Japan
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Abstract |
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Introduction |
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Gatifloxacin, a new 8-methoxyquinolone, has a broad spectrum of activity with expanded potency against Gram-positive cocci.58 In this study, we examined the in vitro activity of gatifloxacin against recent clinical pathogens isolated from patients with respiratory tract, urinary tract or surgical infections in Japan, and compared it with that of other quinolones and structurally unrelated antimicrobial agents.
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Materials and methods |
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Gatifloxacin, levofloxacin, ciprofloxacin and sparfloxacin were synthesized at Kyorin Pharmaceutical Co., Ltd (Tokyo, Japan). Oxacillin, penicillin G, ampicillin, cefaclor and minocycline were purchased from Sigma Chemical Co. (St Louis, MO, USA), and clarithromycin was obtained from Dainabot Co., Ltd (Tokyo, Japan).
Bacterial strains
All 873 clinical strains used in this study were isolated from patients with respiratory tract, urinary tract or surgical infections during 19971998 in Japan.
Susceptibility testing
MICs were determined by a two-fold agar dilution method with MuellerHinton medium (Difco, Detroit, MI, USA) and an inoculum of approximately 1 x 104 cfu/spot as recommended by the Japan Society of Chemotherapy.9 This medium was supplemented with 5% defibrinated horse blood for streptococci, Enterococcus faecalis and Moraxella catarrhalis, and with 5% Fildes extract (Oxoid, Basingstoke, UK) for H. influenzae. Chocolate agar was used for Neisseria gonorrhoeae. H. influenzae and N. gonorrhoeae were incubated in a CO2 incubator. For the detection of methicillin-resistant staphylococci, oxacillin was used with salt agar (2% NaCl) incubated at 32°C. ß-Lactamase production was assessed using nitrocefin-impregnated sticks (Oxoid).
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Results and discussion |
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The activity of gatifloxacin against Enterobacteriaceae was comparable to that of the other quinolones. All isolates of Escherichia coli and Klebsiella pneumoniae from respiratory tract infections were inhibited at 0.78 mg/L of gatifloxacin. The MIC90s for Pseudomonas aeruginosa were 3.13 mg/L for respiratory and surgical pathogens and 100 mg/L for uropathogens. H. influenzae and M. catarrhalis were highly susceptible to gatifloxacin, with MIC90s of 0.025 and 0.05 mg/L, respectively. The activity of gatifloxacin was two- to four-fold higher than that of levofloxacin and ciprofloxacin against N. gonorrhoeae. Gatifloxacin activity was roughly comparable to that of the other quinolones against Gram-negative organisms.
In this study, gatifloxacin showed potent in vitro antibacterial activity against the majority of recent Japanese clinical isolates of MSSA, streptococci, E. coli, K. pneumoniae, M. catarrhalis, H. influenzae and N. gonorrhoeae. In particular, all isolates of H. influenzae, S. pneumoniae and M. catarrhalis, major causative pathogens of respiratory infections, were susceptible to0.39 mg/L of gatifloxacin.
We determined the MIC of gatifloxacin for recent clinical isolates from various clinical fields separately. Compared with the respiratory or surgical pathogens, most of the isolates from urinary tract infections were less susceptible to quinolones. This decline in the susceptibility of urinary isolates could be associated with the selection of resistant mutants caused by exposure to the drug.
Highly quinolone-resistant strains were observed in staphylococci, E. faecalis, the Enterobacteriaceae and P. aeruginosa. Gatifloxacin was more potent than the other quinolones against these resistant strains, except for P. aeruginosa, while it showed comparable activity against quinolone-susceptible Gram-positive and/or -negative strains. The finding that quinolone-resistant strains showed incomplete cross-resistance to gatifloxacin suggests a difference in the mode of action between gatifloxacin and other quinolones. Fukuda et al.7 have reported that gatifloxacin is more potent than other quinolones against quinolone-resistant S. aureus possessing mutations in grlA and gyrA, encoding the quinolone target enzymes topoisomerase IV and DNA gyrase, respectively, and overproducing NorA protein, which functions as an efflux pump. The findings obtained in this study with clinical isolates are consistent with the results of Fukuda et al.7
Of 42 S. pneumoniae strains, eight (19%) were resistant to penicillin G (MIC0.78 mg/L), six (14%) to clarithromycin (MIC
1.56 mg/L) and 29 (69%) to minocycline (MIC
1.56 mg/L). Gatifloxacin showed good activity against S. pneumoniae strains resistant to these drugs; it also showed good activity against seven strains of ampicillin-resistant H. influenzae (MIC of ampicillin
1.56 mg/L, one of which was ß-lactamase positive) with MICs of 0.01250.25 mg/L.
The maximum serum concentration of gatifloxacin is 1.71 mg/L and its elimination half-life is 78 h, with a mean peak urinary concentration of 240 mg/L after a single oral administration of 200 mg in humans.10 The in vitro antibacterial activity of gatifloxacin described in this study, together with its favourable pharmacokinetic profile, indicate that gatifloxacin may be useful in the treatment of infections caused by various pathogens, including drug-resistant strains.
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Acknowledgments |
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Notes |
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References |
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Fukuda, H., Hori, S. & Hiramatsu, K. (1998). Antibacterial activity of gatifloxacin (AM-1155, CG5501, BMS-206584), a newly developed fluoroquinolone, against sequentially acquired quinolone-resistant mutants and the norA transformant of Staphylococcus aureus. Antimicrobial Agents and Chemotherapy 42, 191722.
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9 . Japan Society of Chemotherapy. (1981). Standard method of MIC determinations. Chemotherapy 29, 769.
10 . Nakashima, M., Uematsu, T., Kosuge, K., Kusajima, H., Ooie, T., Masuda, Y. et al. (1995). Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans. Antimicrobial Agents and Chemotherapy 39, 263540.[Abstract]
Received 15 July 1999; returned 14 October 1999; revised 24 November 1999; accepted 13 December 1999