Quinolones - Antimicrobics That Act on Cell Wall Synthesis

Quinolones

The quinolones have a nucleus of two fused six-member rings that when substituted with fluorine become fluoroquinolones, which are now the dominant quinolones for treatment of bacterial infections. Among the fluoroquinolones, ciprofloxacin, norfloxacin, and ofloxacin, the addition of a piperazine ring and its methylation alter the activity and phar-macologic properties of the individual compound. The primary target of all quinolones is DNA topoisomerase (gyrase), the enzyme responsible for nicking, supercoiling, and sealing bacterial DNA during replication. Bacterial topoisomerases have four subunits, one or more of which are inhibited by the particular quinolone. The enhanced activity and lower fre-quency of resistance seen with the fluoroquinolones is attributed to binding at multiple sites on the enzyme. This greatly reduces the chance a single mutation can lead to resistance, which was a problem with the first quinolone, nalidixic acid, a single-binding site agent.

The fluoroquinolones are highly active and bactericidal against a wide range of aer-obes and facultative anaerobes. However, streptococci and Mycoplasma are only margin-ally susceptible, and anaerobes are generally resistant. Ofloxacin has significant activity against Chlamydia, whereas ciprofloxacin is particularly useful against P. aeruginosa. Fluoroquinolones has several favorable pharmacologic properties in addition to their broad spectrum. These include oral administration, low protein binding, good distribution to all body compartments, penetration of phagocytes, and a prolonged serum half-life that allows once- or twice-a-day dosing. Norfloxacin and ciprofloxacin are excreted by hepatic and renal routes, resulting in high drug concentrations in the bile and urine. Ofloxacin is excreted primarily by the kidney.