Adverse drug reactions: implications for the development of fluoroquinolones

Quinolone antibacterials, originally derived from anti-malarial compounds, have been developed through side-chain and nuclear manipulation, notably by piperazine and other mono- or bi-cyclic substitutions at the 7 position (giving anti-pseudomonal activity and greater anti-Gram-negative activity) and fluorination at various sites (giving increased anti-Gram-positive activity). The class has now been in clinical use for 40 years. Increased activity has not been without cost: for example, specific idiosyncratic reactions have consigned agents such as the 1-(2,4)-difluorophenyl compounds, such as temafloxacin (haemolytic uraemic syndrome) and trovafloxacin (hepatotoxic reactions), to restriction, suspension or withdrawal. Class adverse drug reactions (ADRs), variable in frequency and severity within the group, have significantly affected individual groups of compounds, such as the 8-chloro derivatives (Bay y 3118, clinafloxacin and sitafloxacin), which, whilst extremely potent, are also highly phototoxic and have largely been discarded.