The fluoroquinolone antibacterials: past, present and future perspectives

Abstract

The history of the development of the quinolones is described from the first quinolone, nalidixic acid, via the first 6-fluorinated quinolone norfloxacin, to the latest extended-spectrum fluoroquinolones. The structural modifications made to the basic quinolone and naphthyridone nucleus and to the side chains have allowed improvements to be made such that the next group of fluoroquinolones after norfloxacin, exemplified by ciprofloxacin, had high activity against Gram-negative species and a number of atypical pathogens, good-to-moderate activity against Gram-positive species and were well absorbed and distributed. These compounds have been successfully used in the clinic for a decade and the size of the market has risen in recent years to only a little less than that for penicillins and macrolides. Notwithstanding the broad spectrum of these compounds, defects became evident. The growth in understanding of structure–activity relationships with fluoroquinolones has enabled the development of even better compounds. The targets in fluoroquinolone research during the last few years include: improvements in pharmacokinetic properties, greater activity against Gram-positive cocci and anaerobes, activity against fluoroquinolone-resistant strains, and improvements in activity against non-fermentative Gram-negative species. The compounds developed in the recent years have fulfilled some but not all of these goals; improved bioavailability is one target achieved with most of the more recent compounds allowing for once-daily dosing. Gatifloxacin, moxifloxacin and trovafloxacin have all greatly improved the activity against Gram-positive cocci, particularly pneumococci, and against anaerobes. They are not quite as active as ciprofloxacin against Enterobacteriaceae, and show no substantial improvements in activity against non-fermentative species. Clinafloxacin, gemifloxacin and sitafloxacin have even better activity against Gram-positive cocci and are as active as ciprofloxacin against most Gram-negatives, though gemifloxacin is less active than the other new compounds against Gram-negative anaerobes. These three compounds do retain some activity against a number of ciprofloxacin-resistant species (Gram-positive and Gram-negative), but whether this activity will be adequate for clinical use is at present unclear. Both clinafloxacin and sitafloxacin contain a chloro substituent at position 8 of the quinolone nucleus. A halogen at this position in a number of compounds, though giving good activity, has also been associated with phototoxicity. Several fluoroquinolones have had to be withdrawn or strictly limited in their use post-marketing and in some cases no obvious relationship can be seen between the adverse effects and structural features, making this an area for urgent research.

Introduction

The earliest antibacterial agents to be used as chemotherapeutic drugs in the 1920s were synthetic agents, the sulphonamides. Since the discovery of penicillin and its entry into clinical use in the 1940s, the field has been dominated over the past 50 years by natural products or their semi-synthetic derivatives. The β-lactams still play a major role in the treatment of bacterial diseases, with macrolides and aminoglycosides also having a substantial share of the market. The fluoroquinolones are the only synthetic antibacterial agents to rival β-lactams for impact in clinical usage in the antibacterial field. In two decades, they have moved from a small, relatively unimportant group of drugs used predominantly for urinary tract infection (UTI), to a class that had worldwide sales of US$3.04 billion in 1997. With the advent of the newer compounds entering the market place, this figure is likely to increase still further. There are now numerous new fluoroquinolones and the structural modifications made have allowed this class to develop from the early compounds of such limited utility, to the latest agents with a remarkably broad spectrum of activity and excellent pharmacokinetics allowing for once-daily dosing and thus improving patient compliance.

Fluoroquinolones have a number of characteristics that have led to their increased use. Like the β-lactams and unlike the macrolides, they have a rapid bactericidal effect against most susceptible organisms, a feature that most believe is of growing importance in the clinic as the numbers of patients who are seriously ill, or have defective or impaired immune systems increase. The fluoroquinolones penetrate into tissues and mammalian cells extremely well, a feature they share with the macrolides. Conversely, the β-lactams penetrate mammalian cells poorly and thus have limited benefit when the pathogen is intracellular.

This article reviews the progress in fluoroquinolone research with respect to the antimicrobial activity of the class. It does not address the equally important aspects of safety, tolerance and drug interactions, all of which have been ably reviewed elsewhere recently [1], [2], [3]. As in any area of research into a drug class, there have been a number of fluoroquinolones that have had unacceptable side-effects, many not reaching the market. A few compounds, such as temafloxacin, have been withdrawn post-marketing, the most recent being trovafloxacin, a compound with an excellent profile in terms of antimicrobial activity and pharmacokinetics, and grepafloxacin. It is to be hoped that further research into the structure–activity relationships of the newer compounds with regard to toxicity may help to avoid such incidences.