Question 6

The development of fluoroquinolones has seen many withdrawn from the market, while levofloxacin has continued to be both effective and well tolerated. Could you discuss the progression of fluoroquinolone development?

Fluoroquinolones were developed after manipulation of the quinolone nucleus, with ofloxacin and ciprofloxacin among the first to be developed, although ciprofloxacin was not recommended for RTI because of a relative lack of activity against S. pneumoniae. In comparison, the racemic ofloxacin was noted to have better Gram-positive coverage. However, both of these agents required twice-daily administration. Following the discovery that the levo-isomer of ofloxacin was the active component, this was purified and marketed as levofloxacin, first in Japan and then globally. Levofloxacin was the first of the respiratory fluoroquinolones, so-called due to their efficacy against a variety of respiratory infections including pneumonia, sinusitis and bronchitis. Although physicians were initially skeptical about the respiratory fluoroquinolones, they were proven to be very effective in this arena, leading to many new agents being developed. However, many of these were soon shown to be associated with unacceptable toxicity leading to their withdrawal. Temafloxacin was associated with significant hematologic toxicity, sparfloxacin caused phototoxicity; grepafloxacin as well as causing cardiotoxicity was not liked by many patients due to an unpleasant taste and trovafloxacin, which originally appeared as a promising gastrointestinal agent due to its Gram-negative and anaerobic activity, was also withdrawn due to toxicity. The latest fluoroquinolone to be withdrawn is gatifloxacin, which was found to be associated with symptomatic hypoglycemia and rebound hyperglycemia as well as some cardiotoxicity. However, throughout this time, levofloxacin has continued to be used and found to be well tolerated. It has now been used extensively throughout the world, with an exceptional post-marketing safety record (12). I have used it a great deal and have seen some cases of insomnia, easily solved by changing the time of administration, but overall, it is a very well tolerated and effective drug.