Levofloxacin has been proven to be a very effective agent in the treatment of respiratory infections. It possesses excellent bactericidal activity against key pathogens, including pneumococcal strains resistant to many other classes of drugs, Haemophilus influenzae, Moraxella catarrhalis and the atypical pathogens including many Enterobacteriaceae. In addition levofloxacin has excellent penetration into both intracellular and extracellular respiratory tissues.

The parameters that predict the likely outcome of fluoroquinolone treatment include the peak concentration over the MIC or the area under the concentration-time curve over MIC. Therefore by using a higher dose, a higher Cmax or AUC over MIC ratio should be achieved. This will increase the speed and extent of bactericidal activity, improve management of difficult to treat pathogens, increase penetration into more tissues, may prevent resistance, and allow shorter duration of therapy compared to standard doses. While not all fluoroquinolones can be safely given in higher doses, it is known that levofloxacin dosage can be increased safely over 500 mg.

Higher rates of clinical success against the pneumococcus are associated with fluoroquinolones that achieve an AUC to MIC ratio of greater than 25-30, and this figure is above 100 for the Gram-negatives. By increasing levofloxacin dosage from 500 to 750 mg, the peak concentration increases by 100% and the AUC over MIC ratio almost doubles from 47 to 91.

A 750 mg dose of levofloxacin was compared with a 500 mg dose against ciprofloxacin-resistant Streptococcus pneumoniae. When the isolate had an MIC for levofloxacin of 1.8, the outcome for the standard and higher dose were similar. However as the MIC increased to 3.2 the 750 mg dose was associated with improved outcome. This is because, in this latter situation, the AUC to MIC ratio associated with the higher dose is above 25, while the lower dose is not.

The 750 mg dose is also more effective in treating Gram-negative infections. This higher dose attains target attainment rates 60% of the time for Pseudomonas aeruginosa, and about 90% for Klebsiella pneumoniae and Enterobacter cloacae, slightly higher than the 400 mg twice-a-day ciprofloxacin regimen. The 750 mg dose has also been shown to be as effective as imipenem cilastatin in nosocomial pneumonia.

A recent study evaluated 750 mg levofloxacin given for five days compared to 500 mg for ten days for community-acquired pneumonia. The clinical outcomes were equivalent in both arms and this was true for all severity of illness, and was not dependent on pathogens.

Patients receiving the high-dose short-course therapy also reported symptom resolution faster than patients in the standard arm. This was true not only for subjective assessment of fever, but also supported by objective temperature measurements. The presence of purulent sputum and dyspnea also resolved faster with the higher dose therapy but the difference was not as significant.

The 750 mg dose was also associated with a shorter use of intravenous therapy and faster switch to oral treatment, which was associated with a cost saving of approximately US$25 per patient.

The tolerability of the higher dose was also very good with the incidence of adverse event, serious adverse event leading to discontinuation of therapy or death was comparable or even less than in patients in the standard arm.

There was no significant difference in the incidence of specific emergent adverse events between the 750 mg dose and data from phase III studies in the US of either the 250 mg dose or 500 mg dose.

Higher-dose levofloxacin therapy achieves significantly higher pharmacodynamic parameters than the 500 mg dose, which predicts good outcomes particularly in patients who have difficult-to-treat pathogens. The higher-dose regimen of levofloxacin will become an attractive therapeutic option for more difficult-to-treat infections in the future.