Fluoroquinolone Generations: What’s Next?

A “generation” is a classification marking an advance in pharmaceutical development within a class of agents. With respect to antibiotics, a modifi cation in chemical structure, a twist in the mechanism of action, a shift or expansion of antimicrobial activity, improved effi cacy, lower resistance, better tolerability, altered pharmacokinetics, or some combination of the above, may solve a problem presented by a prior generation of the medication. Th e class of systemic cephalosporins epitomize the concept of chronologically unfolding generations in antibiotic development, as each new development resulted in a shift in the antimicrobial spectrum toward greater anti-gramnegative and anti-anaerobic activity and improved the range of pharmacokinetic problems associated with the generation before. Th e result is the diverse catalogue of cephalosporin agents in use today, all using a similar mechanism but with unique antibacterial potencies and properties. Th e fl uoroquinolone class expanded in the opposite microbiologic direction, starting as mostly gram-negative, but progressing to increasing gram-positive coverage. And while the categories or generations are perhaps less clear compared to cephalosporins (eg, it is unclear whether levofl oxacin, the levo-isomer of ofl oxacin, is a 2nd or 3rd generation fl uoroquinolone), the idea is basically the same.1 Th e systemic fl uoroquinolones originated in the 1960s with naladixic acid, an anti-gram-negative agent excreted in high concentrations in urine and used principally for the treatment of urinary tract infection. Ensuing fl uoroquinolone generations employed structural modifi cations to achieve varying affi nities for two target enzymes involved in bacterial DNA replication: DNA gyrase (also called topoisomerase II) and topoisomerase IV. Th us, fl uoroquinolone generations evolved from narrow-spectrum antigram-negative activity (1st generation, eg, naladixic acid) to expanded antigram-negative activity including Pseudomonas (2nd generation, eg, ciprofl oxacin) to increasing gram-positive fi ghting activity (3rd generation, eg, levofl oxacin;