Fluoroquinolines: Past, present and future of a novel group of antibacterial agents

American Journal of Pharmaceutical Education, Summer 2002 by Scholar, Eric M

PROLOGUE

The fluoroquinolones are a group of antibiotics that have increased in numbers in recent years. Their usefulness has greatly expanded with the introduction of several new quinolones having improved properties compared to older members. This paper discusses the chemistry, mechanism of action, therapeutic uses, adverse effects and drug interactions of the fluoroquinolones. The advantages of the newer compounds in this group are emphasized. This paper includes material that is presented to second year medical and pharmacy students as part of a joint pharmacology course. The goal of this lecture is to help the student learn the fundamental properties of this important group of antibiotics.

INTRODUCTION

The fluoroquinolones are a relatively new group of broad-spectrum antibacterial agents with a unique mechanism of action. Since the first quinolone, nalidixic acid, was introduced thousands of related quinolone compounds have been synthesized but most have been abandoned before development for several different reasons. A better understanding of structure activity relationships has allowed scientists to modify the basic quinolone structure to enhance or limit the extent of antimicrobial activity and improve properties such as the therapeutic uses, pharmacokinetics, drug interactions and toxicity of the quinolones. The search is continuing to produce the perfect quinolone(1).

These drugs are unique among antibacterials in that they inhibit bacterial topoisomerase enzymes. Although the original quinolones were effective mainly against urinary tract infections and had antibacterial activity mainly against facultatively anaerobic gram-negative organisms, the newer quinolones have a wider clinical use and a broader spectrum of antibacterial activity including gram-positive and gram-negative aerobic and anaerobic organisms. Some of the newer quinolones have an important role in the treatment of community-acquired pneumonia and intra-abdominal infections. As a result of the recent threats of bioterrorism and the presence of anthrax spores in the mail it has come to light that ciprofloxacin is an important drug for the prevention and treatment of this disease. Quinolone resistance is also becoming an increasing problem due to the selective pressure from their extensive use. The newer quinolones have been found to produce additional toxicities to the heart that were not found with the older compounds. The material presented here is from a lecture presented to medical and pharmacy students.

CHEMISTRY

The quinolones that are used clinically are 4-quinolones and contain a carboxylic acid moiety in the three position of the basic ring structure. The main chemical feature that distinguishes fluoroquinolones from the early quinolones is the presence of a fluorine at position six. The quinolones are now classified into first, second, third and fourth generations with nalidixic acid the first quinolone considered as a first generation compound. There are several differences in chemical makeup among the members of the different generations. The most significant differences are between the two early generation compounds and the third and fourth generation quinolones. This last group is significantly different in mechanism of action, antibacterial activity therapeutic uses and in adverse effects. Several reviews have extensively characterized the structure-activity and structure-toxicity relationships of the quinolone antibiotics(2-4). Table I shows the classification of the approved fluoroquinolones. Figure 1 shows the structure of a first, second and fourth generation quinolone with important structural features highlighted. A key change made in progressing from nalidixic acid to the later generation compounds was the addition of a fluorine at position 6 of the 4-quinolone and the replacement of the 7-methyl side-chain of nalidixic acid with a piperazine group. These changes enhanced antibacterial activity markedly. The addition of the cylcopropyl group in compounds like ciprofloxacin resulted in agents with greater bioavailability. Modifications made in the piperazine group in the third and fourth generation compounds resulted in enhanced activity against streptococcal organisms. Enhanced activity vs.anaerobes resulted from changes such as the addition of the 8-methoxy group in gatifloxacin.

ANTIMICROBIAL PROPERTIES

As a group, the fluoroquinolones have excellent in vitro activity against a wide range of both gram-positive and gram-negative bacteria(5,6). Significant differences in antibacterial activity exist among the different fluoroquinolones some of which have broad-spectrum activity against both gram-negative and gram-positive species(7,8). Some of the fluoroquinolones such as norfloxacin and lomefloxacin however, are less active against gram-positive pathogens.

In general, the fluoroquinolones are less active against staphylococci and streptococci than against the aerobic gramnegative rods. Until the introduction of the newer fluoroquinolones, these drugs did not have reliable activity against gram-positive bacteria and they were not considered suitable for infections such as the empiric treatment for suspected pneumococcal pneumonia(9). However, the newer quinolones are more active here, with clinafloxacin being the most active and trovafloxacin, grepafloxacin, sparfloxacin, moxifloxacin and gatifloxacin also having good activity against these organisms(7,10-12). Somewhat less active are ciprofloxacin and ofloxacin, although they have significant activity against most Staphylococcus aureus isolates, including methicillin-sensitive and penicillin-sensitive strains. Although quinolones demonstrated acceptable activity against methicillin-resistant Staph. aureus when they were first available, they are no longer reliably active against these organisms(13). The older quinolones have only marginal activity against Streptococcus pneumoniae (pneumococci). On the other hand most of the newer quinolones, including trovafloxacin, clinafloxacin, moxifloxacin, sparfloxacin, grepafloxacin, temafloxacin and ofloxacin, are very active against S. pneumoniae, with the potencies for these compounds being several fold greater than those seen for ciprofloxacin and ofloxacin.