Impact of chemical structure on quinolone potency, spectrum and side effects

Following the discovery of nalidixic acid in 1962, numerous structural modifications have been made to the quinolone nucleus to increase antimicrobial activity and improve pharmacokinetic performance. A major advance occurred during the 1980s with the discovery that a fluorine at position 6 conferred broad and potent antimicrobial activity, (e.g. norfloxacin) but still with relatively less activity for Gram-positive and anaerobic organisms than Gram-negative bacteria. Subsequent developments produced quinolones with further improvements, predominantly in either solubility (e.g. ofloxacin), antimicrobial activity (e.g. ciprofloxacin) or prolonged serum half-life (e.g. pefloxacin). Recent modifications have attempted to achieve an optimal blend of favourable properties together with minimal potential for undesirable side-effects. An example is temafloxacin with comparatively enhanced activity against Gram-positive pathogens, a balanced pharmacokinetic profile, minimal CNS penetration, and without interaction with theophylline elimination. Improvements in antimicrobial activity combined with adequate blood and tissue concentrations do offer expectancy of enhanced therapeutic efficacy for new derivatives in those infections by organisms which are 'marginally' sensitive to currently used quinolones. The possibility of resistance emerging in these organisms during treatment, should also be reduced.