Journal of Antimicrobial Chemotherapy (2000) 46, 1-2
© 2000 The British Society for Antimicrobial Chemotherapy
Introduction
Department of Microbiology, City Hospital Trust, Birmingham, UK
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Introduction |
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 Top Introduction |
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From the perspective of antimicrobial chemotherapy, certain parallels are apparent between the advances we are witnessing in the development of fluoroquinolones and those we have seen in the ß-lactams. From parent compounds such as penicillin or 7-amino cephalosporanic acid, agents have been developed with enhanced antibacterial spectra and clinical uses have changed beyond the wildest dreams of the discoverers of the original compounds.
The fluoroquinolones can be said to have had their birth in the ‘vital dyes’ produced in the early years of the twentieth century. From agents such as mepacrine, chloroquine was developed and, from this, the quinolines and quinolones. The first of the quinolones, nalidixic acid, was introduced for clinical use in 1962. Current antimicrobial agents were developed following fluoridation of the quinolone molecule at the C-6 position (and, thus, the discovery of norfloxacin). Dr P. Ball discusses these in some detail.
The Figure
shows the quinolone agents marketed or under clinical trial as an evolutionary ‘tree’. It is important to remember that there are two main branches to this ‘tree’: firstly, the naphthyridine series, which have nitrogen atom at the C-8 position and are represented by nalidixic acid, enoxacin, tosufloxacin and trovafloxacin; all others are fluoroquinolone agents, with the C-7 position being the most adaptable site for chemical change.
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Until recently, the quinolones were primarily compounds with high activity against Gram-negative bacilli but with questionable utility against some important Gram-positive pathogens. For example, there was considerable debate as to whether ciprofloxacin was reliable for use in the treatment of serious pneumococcal disease. These older compounds have, therefore, found considerable use in the treatment of hospital-acquired infection. To meet changing clinical needs, the pharmaceutical industry has developed agents with enhanced activity against Gram-positive pathogens. The major clinical challenge is, of course, the increasing antimicrobial resistance found world-wide in pneumococci. Another change has been a general increase in the elimination half-life of the newer quinolones. Gemifloxacin is the most active anti-pneumococcal fluoroquinolone produced to date and has a half-life such that once-daily dosing is possible.
Unless we wish to witness increasing fluoroquinolone resistance among the pneumococci, the medical profession will have to learn to use the newer fluoroquinolones in a timely and prudent fashion. Undoubtedly the new agents will enjoy greater use in the treatment of respiratory tract infections and L. Mandell discusses their responsible use in these common diseases. A knowledge of their in vitro activities (discussed by G.-C. Schito) will need to be combined with evidence from the emerging science of antibacterial pharmacodynamics, which is described here by G. Woodnutt. There is new information about how fluoroquinolones act and how resistance emerges. From this, it appears that the most efficient use of these compounds is to employ a highly active agent with good pharmacodynamics (such as a high AUIC) for the shortest period of time consistent with cure. Only then can we ensure that this important group of agents retains its usefulness well into the twenty-first century.
Clinical trials of gemifloxacin are currently in progress and their detailed results are awaited. Preliminary information suggests that gemifloxacin is both efficacious and well tolerated in the treatment of respiratory tract infections.
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* Tel: +44-121-554-3801; Fax: +44-121-551-7763.
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