The Fluoroquinolones: The Last Samurai?

Since the serendipitous discovery of the initial member of the quinolone class of drugs in 1962, these antimicrobials have become some of the most widely used and most effective antibacterial agents in the world. In the first article in this supplement, Dr. Vincent Andriole [1] notes that, since the discovery of the first “quinolone” (i.e., nalidixic acid, which is not really a quinolone but, rather, a naphthyridine derivative), there have been numerous modifications of the basic naphthyridine and quinolone nuclei of these compounds to produce more-effective, less-toxic antimicrobials. At the top of the developmental hierarchy of the quinolones are several modern fluoroquinolones, including gatifloxacin, gemifloxacin, and moxifloxacin. These 3 agents possess outstanding activity against respiratory pathogens, methicillin-susceptible staphylococci, and a variety of important gram-negative bacilli. Gatifloxacin and moxifloxacin are also active against a variety of anaerobes. Because of the widespread application of these drugs, it seems reasonable now to reassess one of the most important of these new compounds—moxifloxacin. This drug was developed by scientists at Bayer Pharmaceuticals in the early 1990s and was first approved for marketing in Germany and the United States in 1999. Thus, at its “5-year anniversary,” it seems reasonable to reassess this compound in association with the other modern fluoroquinolones and to determine its usefulness in treating a variety of respiratory tract and other infections.

In the second article in this supplement, Dr. George Jacoby [2] highlights the mechanism of action of the fluoroquinolones and provides new and important information concerning mechanisms of resistance (including transferable plasmid-mediated resistance) to the fluoroquinolones. Next, Dr. Brian Wispelwey [3] describes the clinical implications of the pharmacokinetics and pharmacodynamics of the fluoroquinolones. Dr. Susan L. Davis et al. [4] review the pharmacoeconomic issues associated with the clinical application of these agents. Dr. Robert Owens [5] provides useful information on the safety profile of the fluoroquinolones, in general, and of the newer agents, in particular. Next is a series of specific articles on the clinical use of the fluoroquinolones in the treatment of respiratory tract infections. Dr. Michael Neiderman [6] summarizes the current guidelines and recommendations for the use of moxifloxacin and other fluoroquinolones in the treatment of community-acquired pneumonia. The role of the new fluoroquinolones in the treatment of acute bacterial sinusitis is covered in detail by Dr. Jack Anon [7]. Finally, Dr. Sanjay Sethy [8] provides an in-depth look at the role of moxifloxacin and other fluoroquinolones in the treatment of acute exacerbations of chronic bronchitis.

It has been >40 years since the discovery of nalidixic acid. During that time, chemical modification of the naphthyridine and quinoline nuclei has resulted in a broad variety of useful fluoroquinolone antimicrobials, culminating in the development of such drugs as gatifloxacin, gemifloxacin, and moxifloxacin. Although attempts to further chemically modify this drug class to develop more-effective, less-toxic agents continue, the number of ideas for new compounds appears to be relatively small at the present time. One of the most promising new ideas, which is based on the notion of removing the fluorine atom from position 6 of the molecule (resulting in “6-desfluoro” compounds), has resulted in compounds that have produced major challenges during clinical development, and the future of this class of quinolone antimicrobials is not clear at the present time. Thus, it appears that the currently available agents will be the mainstays of fluoroquinolone-based therapy for years to come. Given this fact, it is important to understand clearly the clinical settings in which fluoroquinolones are drugs of choice or are important alternatives in the treatment of bacterial infections. Appropriate use of these compounds can minimize the selective pressures that, in turn, lead to the development of resistance, and it can preserve the lifetime of this incredibly valuable class of compounds. It is particularly important to preserve the lifetime of this class of drugs, since it has become clear during the past decade that the search for new antimicrobials with unique mechanisms of action is becoming more and more difficult, resulting in an overall decrease in the number of new antibacterial agents currently in development.

Acknowledgment

Potential conflicts of interest. R.C.M., Jr.: consultant for Bayer, Aventis, and Pfizer.