Introduction

The development of quinolone antibacterials, since the discovery of the naph-thyridine agent nalidixic acid some 40 years ago [1], has progressed with periods of great clinical innovation, alternating with periods of apparent inactivity following unexpected recognition of rare, but severe, adverse reactions associated with specific agents. Initially, within a decade, the 4-quinolones oxolinic acid and cinoxacin, which had improved activity against a limited range of Gram-negative bacteria, had been synthesized. Parallel developments in Japan had yielded 7-piperazine-substituted compounds, such as pipemidic acid, which had limited activity against Pseudomonas aeruginosa. However, the breakthrough to broad-spectrum activity waited a further 10 years before fluorination, primarily at the 6-position, resulted in the fluoroquinolones. It is difficult to overestimate the clinical impact of the development of these agents.

Since the mid-1980s, the fluoroquinolones have become a major group of synthetic antibiotics with activity that ranges from the Enterobacteriaceae and opportunists such as Pseudomonas aeruginosa, to Gram-positive pathogens, including streptococci and staphylococci. These changes resulted in agents—for example, ciprofloxacin and ofloxacin (later the levo-isomer levofloxacin)—that are applicable across a broad range of indications, including those involving the genitourinary, respiratory, and gastrointestinal tracts, skin and soft tissues, and other structures. In most bodily tissues and fluids, the fluoroquinolones are characterized by excellent penetration and therapeutic ratios. Ciprofloxacin and ofloxacin revolutionized the management of many conditions previously amenable only to intravenous therapy or in which management has been compromised by bacterial resistance to standard agents, such as the P-lactams. Important examples include pyelonephritis, enteric fevers, prostatic infections, pulmonary exacerbations of cystic fibrosis, and nosocomial pneumonias.

The next significant advance occurred in the early 1990s with the synthesis of temafloxacin, which had four- to eightfold greater activity against Streptococcus pneumoniae and good activity against anaerobes, such as the Bacteroides and Prevotella spp. However, unexpected toxicity, in the form of hemolytic uraemic syndrome [2], resulted in its withdrawal only months after launch. In addition, the development of several other compounds with even greater anti-Gram-positive potency, notably sparfloxacin, sitafloxacin, and Bay 3118, has been either delayed or discontinued due to an unacceptable incidence of phototoxicity (and other adverse effects). By the mid-1990s, clinical development appeared to have halted, although molecules with differing sidechains and laboratory activity continued to be synthesized.

However, optimism again increased with the discovery of trovafloxacin, clinafloxacin, and grepafloxacin, only to be dampened at the end of the decade by their abrupt withdrawal or suspension due to rare but severe adverse effects, including hepatotoxicity (trovafloxacin), significant QT prolongation and associated cardiac deaths (grepafloxacin), and serious phototoxicity and hypoglycemia (clinafloxacin). All of these agents had significantly greater potency against Gram-positive species, notably S. pneumoniae, and in the case of trovafloxacin at least proved highly clinically effective in pneumococcal infections. At a time when burgeoning global multidrug resistance among pneumococci had begun to compromise traditional therapy, this left a considerable hiatus in the range of potential alternatives to penicillin and macrolides.

Fortunately, the 8-methoxyquinolones moxifloxacin and gatifloxacin, which are highly potent against S. pneumoniae (10-fold greater than the earlier second-generation agents), clinically effective, and appear free from either significant or unexpected toxicity, have filled this therapeutic vacuum. Their proven activity against S. pneumoniae, coupled with maintained high potency against Haemophi-lus influenzae and Moraxella catarrhalis, and excellent penetration into respiratory tissues, including the intracellular habitat of Chlamydia and Legionella spp., suggests that, where ciprofloxacin was considered by many to be inappropriate for respiratory infections, 8-methoxyquinolone derivatives will now become agents of choice. They appear to limit emergence of resistance in Gram-positive species, which could prove a major advantage, compared with levofloxacin, which has also proven surprisingly clinically effective in respiratory infections despite a pneumococcal MIC typical of earlier second-generation agents. Further progress includes continued development of the naphthyridone subclass, notably gemifloxacin, which is characterized by a further 10-fold increase in anti-pneu-mococcal potency. Clinical trial results are awaited with interest.

The fluoroquinolones and their precursors have a number of predictable structure-activity and structure-adverse effect relationships relating to nuclear and sidechain configurations. Thus, design of new molecules can avoid many of the problems that have characterized previous members of the group. It may be anticipated that further modifications to the molecular structure will improve spectrum and activity while reducing the incidence of adverse effects.

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