The dwindling supply of new antibiotics largely reflects regulatory and commercial challenges, but also a failure of discovery. In the 1990s the pharmaceutical industry abandoned its classical ways of seeking antibiotics and instead adopted a strategy that combined genomics with high-throughput screening of existing compound libraries. Too much emphasis was placed on identifying targets and molecules that bound to them, and too little emphasis was placed on the ability of these molecules to permeate bacteria, evade efflux and avoid mutational resistance; moreover, the compound libraries were systematically biased against antibiotics. The sorry result is that no antibiotic found by this strategy has yet entered clinical use and many major pharmaceutical companies have abandoned antibiotic discovery. Although a raft of start-up companies-variously financed by venture capital, charity or public money--are now finding new antibiotic compounds (some of them very promising in vitro or in early trials), their development through Phase III depends on financial commitments from large pharmaceutical companies, where the discouraging regulatory environment and the poor likely return on investment remain paramount issues.

The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin and CNS, and are mainly mild and reversible. Of the gastrointestinal events, nausea and vomiting are the most common. Mild hepatic reactions are a class effect, usually presenting as mild transaminase level increases without clinical symptoms. However, postmarketing surveillance has revealed significant hepatotoxicity with trovafloxacin. It is not currently known whether the severe reactions to trovafloxacin are specific to that agent or simply represent an extreme of an emerging class effect. The enormous worldwide usage of, and extensive published adverse effect data on the other fluoroquinolones and naphthyridones suggests the former. In perspective, rare but serious hepatotoxicity has been reported with other fluoroquinolones and the overall incidence of trovafloxacin hepatotoxicity is not dissimilar to that reported with flucloxacillin and amoxicillin-clavulanic acid. CNS reactions vary in severity and include dizziness, convulsions (notably with lomefloxacin) and psychoses. Fluoroquinolones differ in their pro-convulsive activity, relating to their differing potential as gamma-aminobutyric acid antagonists and binding to the N-methyl-D-aspartate receptor. The basis for the increased seizure potential following the coadministration of nonsteroidal anti-inflammatory drugs with certain fluoroquinolones is not fully understood. Fluoroquinolone phototoxicity, caused by the generation of toxic free oxygen species under exposure to UVA radiation, is significantly more common with 8-halogenated compounds. Certain patient groups, e.g. patients with cystic fibrosis, are predisposed to this adverse effect. Murine photocarcinogenicity has been demonstrated with lomefloxacin, but no such effects have been reported in humans. Prolongation of the QTc interval is also a class effect, although cardiac arrhythmias have only been linked with sparfloxacin. Among the newer fluoroquinolones, clinically significant cardiac events are rare or absent but possible interactions in patients receiving other drugs capable of causi ng QT prolongation should be anticipated. Tendinitis and rupture, usually of the Achilles tendon, are rare, class-effects of fluoroquinolones, most frequently reported with pefloxacin. Predisposing factors include aging, corticosteroid use, renal disease, haemodialysis and transplantation. Use of fluoroquinolones in paediatric patients remains contentious. However, accruing human data suggest that restrictions on paediatric use imposed because of fluoroquinolone-induced cartilage damage in juvenile animals, may soon be relaxed. Data from over 1700 children in the UK failed to disclose arthropathy and extensive paediatric use of norfloxacin in Japan and ciprofloxacin in developing countries has been free of articular effects.

The fluoroquinolone class of antimicrobials has been in clinical use for over 13 years. During that period, some representatives of the class have been extensively prescribed, such as ciprofloxacin and levofloxacin, while others have seen minimal use and have been restricted or withdrawn, namely, trovafloxacin and grepafloxacin. Manipulation of the fluoroquinolone structure by substituting a range of moieties around the core has yielded enhanced antibacterial activity, but in some cases this has come at a price. Specific substitutions are discussed in relation to particular recognized adverse events. In the present paper, newly introduced fluoroquinolones, such as moxifloxacin and gatifloxacin, are examined in terms of anticipated class effects and recent clinical experience. These antimicrobials are associated with reactions such as diarrhea, nausea, headache and other typical antimicrobial phenomena at rates less than 5%. New fluoroquinolone agents should be examined carefully in light of structural findings until adequate clinical data are amassed.

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New fluoroquinolones have been in clinical use for 10 years and have an excellent record of safety and tolerance. The main elements of their adverse reaction profile were predictable from human experience with precursor naphthyridines and quinolones, and from toxicological studies in animals. Thus gastrointestinal reactions (1 to 5%), skin disturbances (less than 2.5%) and central nervous system (CNS) effects (usually around 1 to 2%) were anticipated. Individual group members exhibit particular properties in relation to their chemical structures, for example the phototoxicity associated with 8-halogenation of the nucleus and found to be a particular problem with lomefloxacin and sparfloxacin. Other members, for example ofloxacin, are linked to a higher than usual incidence of CNS reactions and psychological disturbance. However, despite increasing usage, none of the present group have been implicated in joint damage in children, which had been a major concern following reports of this effect in juvenile animals in chronic toxicity studies. Furthermore, intravenous formulations appear to have no associated increase in toxicity. Crystalluria with associated renal damage, originally thought likely to limit intravenous dosage, has not proved to be a problem in humans. Clinically significant interactions may occur but, as with those involving various NSAIDs and potentially leading to convulsions, they have been defined and are thus avoidable. Postmarketing surveillance studies and prescription event monitoring have largely confirmed the limited adverse reaction profile defined during clinical trials. However, some unexpected reactions have appeared after launch, most notably the episodes of haemolysis, renal failure and hypoglycaemia which led to the withdrawal of temafloxacin. These effects have not been observed with other fluoroquinolones. However, severe tendinitis appears to be a group effect, albeit rare, and anaphylactoid reactions have been reported with several of the fluoroquinolone group, often in AIDS patients. The new fluoroquinolones are essentially a well tolerated group of antibacterials, the benefits of which clearly outweigh their disadvantages in a wide range of indications. Clinical efficacy has been a larger determinant of which members have succeeded in the marketplace than potential toxicity. However, the lesser potential for adverse effects of some of the class, e.g. norfloxacin, ofloxacin and ciprofloxacin, has undoubtedly led to their more widespread use. For others, e.g. enoxacin, limited clinical utility and a perception of increased toxicity have resulted in sidelining. There remains the potential for development of safer and yet more active fluoroquinolones via chemical manipulation both of the nucleus and the side chain substituents.