Department of Medical Microbiology, City Hospital NHS Trust, Birmingham B18 7QH, UK
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Abstract |
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Introduction |
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Materials and methods |
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Approval for this study was granted by the Hospital Ethics Committee and all volunteers gave written informed consent. All volunteers underwent a full history and examination, including ECG, and were shown to have normal haematological and biochemical profiles and normal urinalysis.
On the evening before the study, two 1 cm2 0.2% cantharidine-impregnated plasters were attached to the subjects' forearms to induce blister formation. Plasma samples were obtained from the contra-lateral arm following insertion of an iv catheter kept patent by flushing with 0.9% saline (Antigen Pharmaceuticals, Rosecrea, Ireland).
The dose was given to the fasting subjects with 200 mL of water. The subjects then fasted for a further 3 h when a light breakfast was given. A further 2 h later fluid and food was allowed ad libitum. About 10 mL of venous blood was collected before the dose, then 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 h post dose.
Between 50 and 100 µL of inflammatory fluid was aspirated with a fine needle before administration of the dose and then at 0.5, 1, 1.5, 2, 4, 6, 8 12 and 24 h. The blister was re-sealed with a plastic spray dressing (Opsite, Smith & Nephew, Hull, UK). Urine was collected 04, 48, 812, 1224 h post dose. At 30 h post dose the routine haematological and biochemical tests were repeated.
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Drug analysis |
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The lower limit of detection was 0.06 mg/L. The between-assay coefficients of variation were 9.5% and 10.1% for concentrations of 0.2 mg/L and 1.5 mg/L, respectively and the correlation coefficient r2 (calibration curves) over a concentration range of 0.132 mg/L was 0.9617.
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Pharmacokinetic analysis |
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Results |
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Gatifloxacin penetrated into the inflammatory fluid moderately rapidly, the mean Tmax being 4.2 h. Individual variation was large, with a minimum of 1.5 h and a
maximum of 8 h. The mean Cmax in the inflammatory fluid was 3.6 mg/L
(range 2.27.6 mg/L). The mean elimination half-life of gatifloxacin from the
inflammatory exudate was slightly greater than that from plasma (7.2 h). The individual variation
was greater in the inflammatory fluid data than in the plasma data. The mean percentage
penetration of gatifloxacin into inflammatory fluid, calculated by comparing the AUC0 for measurements taken in the inflammatory exudate with that for
measurements taken in plasma was 117.0%, range 138.5103.7.
The mean urinary excretion of the drug in the 24 h following the oral dose was 65%; however, one volunteer excreted only 29.6% and collection may have been incomplete. If these data are removed the mean excretion is 69.4%. Physical examination revealed no abnormalities attributable to gatifloxacin administration. The biochemical haematological and ECG parameters studied revealed no abnormalities. One volunteer complained of a headache starting 8 h post dose which resolved 2 h later after administration of 1 g paracetamol.
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Discussion |
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Fluoroquinolones penetrate into inflammatory exudate to varying extents, ranging from 64%
in the case of trovafloxacin5 to 133% for grepafloxacin,7 the greater protein binding of the former being a possible
explanation for the difference. The protein binding of gatifloxacin is 20%.9 The extent of penetration of gatifloxacin, 117%, is very similar to that of
ciprofloxacin and sparfloxacin (103% and 117%, respectively). As the mean 24 h concentration
in the inflammatory fluid was c. 0.4 mg/L, and the MICs of 90% of S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Chlamydia spp.
and the majority of the Enterobacteriaceae are 0.39 mg/L.2
This suggests that a wide range of organisms should be amenable to treatment.
There is work to suggest that certain pharmacodynamic parameters will be predictive of clinical response. The ratio of AUC to the MIC (AUIC) is said to reflect clinical efficacy. For S. pneumoniae this ratio is c. 80 for gatifloxacin; greater than that obtained with ciprofloxacin given as a 500 mg oral dose (AUIC = c. 60).8 The ratio of MIC to the Cmax is thought to be relevant in the prevention of the emergence of resistance. For gatifloxacin this ratio is c. 10, again approximately twice that of ciprofloxacin. These data suggest both that gatifloxacin will be successful in the treatment of respiratory tract infections caused by the pneumococcus, and that resistance will be less likely to emerge with the new compound in comparison with less active established agents.
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Acknowledgments |
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Notes |
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References |
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2 . Wakabayashi, E. & Mitsuhasi, S. (1994). In vitro activity of AM-1155, a novel 6-fluoro-8 methoxy quinolone. Antimicrobial Agents and Chemotherapy 38, 594601.[Abstract]
3 . Lorber, S., Ziege, S., Ran, M., Scheiber, G., Koeppe, P. & Lode, H. (1998). Gatifloxacin pharmacokinetics and interaction with Maalox. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract A23, p 7. American Society for Microbiology, Washington, DC.
4 . Stahlberg, H. J., Goehler, K., Guillaume, M. & Mignot, A. (1998). Pharmacokinetics of the R & S enantiomers of gatifloxacin, a new fluoroquinolone antibiotic, following single oral doses to healthy Caucasian volunteers. In Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, 1998. Abstract A25, p. 8. American Society for Microbiology, Washington, DC.
5 . Wise, R., Mortiboy, D., Child, J. & Andrews, J. M. (1996). Pharmacokinetics and penetration into inflammatory fluid of trovafloxacin (CP-99,219). Antimicrobial Agents and Chemotherapy, 40, 479.[Abstract]
6 . Stahlberg, H. J., Goehler, K., Guillaume, M. & Mignot, A. (1997). Multiple dose pharmacokinetics and excretion balance of gatifloxacin, a new fluoroquinolone antibiotic, following oral administration to healthy Caucasian volunteers. In Program and Abstracts of the Thirty-Seventh Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Canada, 1997. Abstract A71, p. 14. American Society for Microbiology, Washington, DC.
7 . Child, J., Andrews, J. M. & Wise, R. (1995). Pharmacokinetics and tissue penetration of the new fluoroquinolone, grepafloxacin. Antimicrobial Agents and Chemotherapy 39,513 5.[Abstract]
8 . Schentag, J. J., Nix, E. E. & Forrest, A. (1993). Pharmacodynamics of the fluoroquinolones. In Quinolone Antimicrobial Agents, 2nd edn, (Hooper, D. C. and Wolfson, J. S., Eds), American Society for Microbiology, Washington DC.
9 . 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 39,2635 40.[Abstract]
Received 24 February 1999; returned 5 May 1999; revised 20 May 1999; accepted 29 June 1999