There is increasing recognition that the pharmacokinetic/pharmacodynamic (PK/PD) profile of a drug determines clinical, bacteriological and pharmacoeconomic outcomes as well as relating to the emergence of resistance.

Studies have identified the peak/MIC ratio and 24 hr AUC/MIC ratio as important determinants of fluoroquinolone efficacy. Investigation into the relationship between 24 hour AUC and survival have found that for S. pneumoniae infections, a 90-100% survival rate is achieved when the AUC /MIC ratio is greater than 25. When dealing with Gram-negative bacilli, the AUC/MIC ratio needs to be over 100 to achieve these high success rates. Clinical data confirms that both peak and AUC are highly correlated with outcome, although the peak/MIC ratio is a slightly better predictor of efficacy.

Further clarification of the correlation between peak/MIC ratio has revealed a value of 12.2 (equivalent to a 24 hr AUC/MIC ratio of 100) is associated with a statistically significant difference in outcome, representing 99% and 100% clinical and bacteriological cure rates, respectively.

While efficacy is important, this has to be balanced by safety. The major adverse events with levofloxacin have been gastrointestinal, CNS and skin, with no increase noted for higher doses. Looking in more detail at the incidence of gastrointestinal side effects associated with levofloxacin, it becomes obvious that most of these are minor with relatively low rates. Nausea and diarrhea occur in 1.2% of cases, abdominal pain and dyspepsia in 0.3%, and vomiting in 0.2%.

Hepatic adverse drug events associated with levofloxacin are low with a serious toxicity rate of less than 1 per million, reflecting its minimal liver and biliary metabolism.

In regard to CNS side effects, the modest penetration of levofloxacin into the cerebrospinal fluid may explain the low CNS adverse event rate associated with this agent. It is associated with dizziness and convulsions in extremely low numbers, with convulsions reported in less than 2 per million prescriptions.

Phototoxicity is also low at less than 1 per million prescriptions.

Thus, in terms of pharmacodynamics, levofloxacin is a drug that produces high antimicrobial levels in plasma. In fact, peak levels and AUC obtained with levofloxacin are highest among the various fluoroquinolones, resulting in high antimicrobial levels at the site of infection and excellent efficacy. Fortunately, since the drug is not metabolized by the liver, is excreted in the bile, and has low penetration into the cerebrospinal fluid, it is associated with a low risk of side effects.